Peptidic compounds

ABSTRACT

The present invention provides a compound of formula (I), (II), (III) and (IV) as defined herein and pharmaceutically acceptable derivatives thereof. The present invention further provides use of the compounds of the present invention in the treatment of bacterial infection and in the treatment of HIV infection. Also provided are pharmaceutical compositions comprising the compounds of the present invention.

FIELD OF THE INVENTION

This invention relates to novel peptidic compounds, methods forpreparing them and their use as antibiotics and in the treatment of HIVinfections.

BACKGROUND OF THE INVENTION

Bacteria and the bacterial infections that can be treated by antibioticsinclude, but are not limited to the following:

Staphylococcus aureus, (or “staph”), are bacteria commonly found on theskin and in the noses of healthy people, (F) and are one of the mostcommon causes of skin infections and can also cause serious andsometimes fatal infections (such as bloodstream infections includingtoxic shock syndrome, impetigo, surgical wound infections, infections ofplastic implants, osteomyelitis and pneumonia).

Enterococci, which have been known as a cause of infective endocarditisfor close to a century, more recently have been recognized as a cause ofnosocomial infection and “superinfection” in patients receivingantimicrobial agents.

Other Gram positive bacteria that can be treated by antibiotics includestaphylococcus epidermitis which causes endocarditis, clostridiumdifficile which causes diarrhea and pseudomembranous colitis, bacillusanthracis of anthrax and streptococcus pneumoniae which causespneumonia, meningitis, septicemia, and childhood otitis media (orear-ache). The family of streptococcus bacteria can also be divided intogroup A or Pyrogenes, which are involved in blood poisoning,glomerularnephritis and fevers such as puerperal, scarlet and rheumaticfever. Group B or streptococcus agalactiae cause neonatal meningitis andpneumonia.

Bacterial Resistance to Antibiotics

Bacterial Infections can occur while in hospital (noscomial), but anadditional problem is the increase of infections that are acquired whilethe person is in the community. A recent study (C) identified theantimicrobial susceptibility profile and resistance mechanisms ofpretreatment MRSA isolates obtained from adult subjects participating inrecent clinical treatment trials of community respiratory infections.Out of 465 S. aureus isolates, 43 were identified as MRSA. Antimicrobialsusceptibility testing indicated susceptibility rates to: vancomycin(100%), gentamicin (86%), clindamycin (39%), quinolones (49%), anderythromycin (12%). All ciprofloxacin-resistant isolates had an aminoacid change in GyrA and GrlA. The results indicate that MRSA from adultsubjects with community respiratory infections have similarantimicrobial susceptibility profiles and resistance mechanisms asnosocomial MRSA.

The pathogenic potential of Staphylococcus aureus in nosocomial andcommunity-acquired infections is well known. When penicillin wasintroduced in mid-1940s, S. aureus was almost 94% susceptible to thisdrug. Widespread resistance to penicillin developed in the 1950s,followed by resistance to semi-synthetic penicillins in the 1960s and1970s. Since then, strains of methicillin-resistant S. aureus andmethicillin-resistant coagulase-neg. staphylococci have spreadworldwide. The prevalence of methicillin-resistant S. aureus variesgeographically. In Argentina it reaches nearly 50%. Methicillinresistance in staphylococci develops due to the additional. penicillinbinding protein PBP2a encoded by gene mecA and is a serious problem bothfor microbiologists and physicians(A). The high prevalence ofmethicillin-resistant staphylococci compromises the use ofsemi-synthetic penicillins for clin. treatments in many institutions,thus increasing the use of vancomycin (a glycopeptide). Until 1996,glycopeptides were almost universally active against S. aureus but itwas then that the first glycopeptide-intermediate S. aureus (GISA) alsoknown as VISA (vancomycin intermediately resistant S. aureus) wasdescribed and isolated in Japan, followed by France and USA. Infectionswith Staphylococcus aureus with reduced susceptibility to vancomycincontinue to be reported, including 2 cases caused by S. aureus isolateswith full resistance to vancomycin. (A) There is alsovancomycin-resistant S. aureus (VRSA) The worldwide increase in theincidence of S. aureus clinical isolates with reduced susceptibility tovancomycin and teicoplanin means that glycopeptide resistance in S.aureus is becoming an important clinical problem.

The exact mechanisms involved have not been elucidated yet, althoughVISA is associated with increased wall synthesis. Many VISA strains arecharacterized by increased cell wall biosynthesis and decreasedcrosslinking of the peptide side chains, leading to accumulation of freeD-alanyl-D-alanine termini in the peptidoglycan, which it has beenproposed can act as false target sites for vancomycin. (B)

The mechanism of vancomycin resistance in enterococcus is well definedand appears to be different to that of VISA.

Vancomycin resistance in enterococci, known as VRE orglycopeptide-resistant enterococci (GRE), exists as either intrinsicresistance where isolates of Enterococcus gallinarum and E.casseliflavus/E. flavescens demonstrate an inherent, low-levelresistance to vancomycin or by acquired resistance where Enterococcibecome resistant to vancomycin by acquisition of genetic informationfrom another organism. Most commonly, this resistance is seen in E.faecium and E. faecalis, but also has been recognized in E. raffinosus,E. avium, E. durans, and several other enterococcal species.

Several genes, including vanA, vanB, vanC, vanD, and vanE, contribute toresistance to vancomycin in enterococci.

E. faecium is the most frequently isolated species of VRE in hospitalsand typically produces high vancomycin (>128 μg/ml) and teicoplanin (>16μg/ml) minimum inhibitory concentrations (MICs). These isolatestypically contain vanA genes. The epidemiology of vancomycin-resistantEnterococcus faecium (VREF) in Europe is characterized by a largecommunity reservoir. In contrast, nosocomial outbreaks and infections(without a community reservoir) characterize VREF in the United States.(G)

In vancomycin-susceptible enterococci, D-alanyl-D-alanine (formed by anendogenous D-alanine-D-alanine ligase) is added to a tripeptideprecursor to form a pentapeptide precursor. The D-Ala-D-Ala terminus isthe target of vancomycin; once vancomycin has bound, the use of thispentapeptide precursor for further cell-wall synthesis is prevented. Inthe VanA phenotype, one of the proteins whose synthesis is induced byexposure of bacterial cells to vancomycin is called VanA; VanA is aligase and resembles the D-alanine-D-alanine ligase from Escherichiacoli and other organisms, including vancomycin-susceptible enterococci.VanA generates D-Ala-D-X, where X is usually lactate; the formation ofD-lactate is due to the presence of VanH, a dehydrogenase encoded byvanH. The depsipeptide moiety, D-Ala-D-Lac, is then added to atripeptide precursor, resulting in a depsipentapeptide precursor.Vancomycin does not bind to the D-Ala-D-Lac terminus, so thisdepsipentapeptide can be used in the remaining steps of cell-wallsynthesis. However, when the normal pentapeptide precursor ending inD-Ala-D-Ala is also present, cells are not fully vancomycin resistant,despite the presence of D-Ala-D-Lac containing precursors. This apparentproblem is taken care of in large part by vanX, which encodes adipeptidase, VanX, that cleaves D-Ala-D-Ala, preventing its addition tothe tripeptide precursor. Should any D-Ala-D-Ala escape cleavage andresult in a normal pentapeptide precursor, vanY encodes an ancillary orback-up function. That is, it codes for a carboxypeptidase, VanY, whichcleaves D-alanine and D-lactate from D-Ala-D-Ala and D-Ala-D-Lactermini, respectively, resulting in tetrapeptide precursors, to whichvancomycin does not bind. The other genes involved in the VanAresistance complex include vanR and vanS, whose encoded proteins areinvolved in sensing the presence of extracellular vancomycin or itseffect and signaling intracellularly to activate transcription of vanH,vanA, and vanX. A final gene in the vanA cluster is vanZ, which encodesVanZ, the role of which is not known. (J)

VanB, encoded by vanB in the vanB gene cluster, is also a ligase thatstimulates the formation of D-Ala-D-Lac. The VanB phenotype is typicallyassociated with moderate to high levels of vancomycin resistance but iswithout resistance to teicoplanin. This is explained by the observationthat vancomycin, but not teicoplanin, can induce the synthesis of VanBand of VanHB and VanXB. However, because mutants resistant toteicoplanin can readily be selected from VanB strains onteicoplanin-containing agar, clinical resistance would likely occuramong VanB strains if teicoplanin were widely used. Most of the proteinsencoded by the vanA gene cluster have homologues encoded by the vanBgene cluster, except for VanZ. The vanB gene cluster has an additionalgene, vanW, of unknown function.

The acquired gene clusters associated with vanA and vanB are found indifferent genetic surroundings. These elements have in turn been foundon both transferable and nontransferable plasmids, as well as on thechromosome of the host strain. VanB type resistance was initially notfound to be transferable, but at least in some instances, the vanB genecluster has been found on large (90 kb to 250 kb) chromosomally locatedtransferable elements, More recently, vanB has been found as part ofplasmids. (I)

In addition to being found in different genetic surroundings, the vanAand vanB gene clusters have also been found in a number of differentbacterial species. vanA has been found in multiple enterococcal speciesas well as in lactococci, Orskovia, and Arcanobacteria (H). Thedistribution of the vanB gene cluster seems somewhat more restricted,having been found primarily in E. faecium and E. faecalis, although ithas recently been found in Streptococcus bovis (H).

The VanC phenotype (low-level resistance to vancomycin, susceptible toteicoplanin) is an inherent (naturally occurring) property of E.gallinarum and E. casseliflavus. This property is not transferable andis related to the presence of species-specific genes vanC-1 and vanC-2,respectively; a third possible species, E. flavescens and its genevanC-3, are so closely related to E. casseliflavus and vanC-2 thatdifferent names are probably not warranted. These species appear to havetwo ligases; the cell-wall pentapeptide, at least in E. gallinarum, endsin a mix of D-Ala-D-Ala and D-Ala-D-Ser. The genes vanC-1 and vanC-2apparently lead to the formation of D-Ala-D-Ser containing cell-wallprecursors, while D-Ala-D-Ala ligases, also present in these organisms,result in D-Ala-D-Ala. The presence of both D-Ala-D-Ala and D-Ala-D-Serprecursors may explain why many isolates of these species testsusceptible to vancomycin and why even those isolates with decreasedsusceptibility display only low-level resistance. (J)

VanD-type glycopeptide resistance has been recently described in an E.faecium isolate from the United States (I). The organism wasconstitutively resistant to vancomycin (MIC>64 μg/ml) and to low levels(4 μg/ml) of teicoplanin. Following polymerase chain reactionamplification with primers that amplify many D-Ala-D-Ala ligases, a605-bp fragment was identified whose deduced amino acid sequence showed69% identity to VanA and VanB and 43% identify to VanC.

Bacterial Resistance to Different Classes of Antibiotics.

As well as resistance to approved beta-lactam, glycopeptide antibiotics(including vancomycin, trade name vancocin), and themacrolide-lincosamide-streptogramins (includingquinupristin-dalfopristin, trade name synercid) (D) various recentfindings have also underlined the importance of biocide resistance as aclin. relevant phenomenon. (D) Outbreaks of biocide-resistant organismsin hospitals have been described and the genetic mechanism forresistance to quaternary ammonium compds. (QACs) in Staphylococcusaureus has now been elucidated.

Some strains of MRSA which have intermediate resistance to glycopeptideswere demonstrated to have decreased susceptibility to some biocidesincluding triclosan for which minimal bactericidal concns. (MBCs)increased from 0.002 to 3.12 mg 1-1. Biocide resistance amongstenterococci has also been demonstrated although there was no clearcorrelation between biocide and antibiotic resistance. The exactmechanisms of resistance in these strains are still being studied but itis clear that biocide resistance is an important clin. phenomenon.

Vancomycin is a cyclic compound. Disclosed herein by reference, WO03/002545 teaches that ‘peptoid compounds’ made from a peptide chaincovalently linked in a cyclic form through a heterocyclic or aromaticring system have antibacterial activity. The reaction know to thoseskilled in the art variously as ‘ring closing metathesis’, ‘Grubbsmetathesis’ or ‘olefin metathesis’ is taught in WO 03/00254 to join theends of the molecule which therefore need to terminate in allyl groups(—CH₂—CH═CH₂) that react in that chemical processes described. Theliterature (J. Bremner et al New J. Chem, 2002, 26, 1549-1551) teachesthat cyclic compounds so made based on a 1,1-binaphthyl scaffold linkedin a ring through the 3,3′-positions can have antibacterial activity.Further this literature describes cyclic molecules made from1,1′-binaphthyl linked through the 2,2′ positions.

Additionally the prior art (J. Bremner et al Tetrahedron, 2003, 59,8741-8755) teaches that related cyclic compounds (therein known as‘carbazole linked cyclic peptoids’) can have antibacterial activity.

There is a need for new compounds which are useful in the treatment ofbacterial infections, especially those caused by vancomycin resistantorganisms.

(A) Staphylococcus aureus with reduced susceptibility to vancomycin.Cosgrove, S. E.; Carroll, K. C.; Perl, T. M. Clinical InfectiousDiseases (2004), 39(4), 539-545.

(B) Morphological and genetic differences in two isogenic Staphylococcusaureus strains with decreased susceptibilities to vancomycin. Reipert,A; Ehlert, Kn; Kast, T; Bierbaum, G. Antimicrobial Agents andChemotherapy (2003), 47(2), 568-576.

(C) Antimicrobial susceptibility and molecular characterization ofcommunity-acquired methicillin-resistant Staphylococcus aureus. Almer,L. S.; Shortridge, V. D.; Nilius, A. M.; Beyer, Jill M.; Soni, Niru B.;Bui, Mai H.; Stone, G. G.; Flamm, R. K Diagnostic Microbiology andInfectious Disease (2002), 43(3), 225-232.

(D) Methicillin-resistant, quinupristin-dalfopristin-resistantStaphylococcus aureus with reduced sensitivity to glycopeptides. Werner,G.; Cuny, C.; Schmitz, F.-J.; Witte, W. Journal of Clinical Microbiology(2001), 39(10), 3586-3590.

(E) Susceptibility of antibiotic-resistant cocci to biocides. Fraise, A.P. Society for Applied Microbiology Symposium Series (2002),31(Antibiotic and Biocide Resistance in Bacteria).

(F) WWW.CDC.gov VISA/VRSA Vancomycin-Intermediate/ResistantStaphylococcus aureus

(G) Epidemic and nonepidemic multidrug-resistant Enterococcus faecium.Leavis H L, Willems R J L, Top J, Spalburg E, Mascini E M, Fluit A C, etal. Emerg Infect Dis. 2003 September Available from: URL:http://www.cdc.gov/ncidod/EID/vol9no9/02-0383.htm (H) Power E G M,Abdulla Y H, Talsania H G, Spice W, Aathithan S, French G L. vanA genesin vancomycin-resistant clinical isolates of Oerskovia turbata andArcanobacterium (Corynebacterium) haemolyticum. J Antimicrob Chemother1995; 36:595-606.

(I) Perichon B, Reynolds P, Courvalin P. VanD-typeglycopeptide-resistant Enterococcus faecium BM4339. Antimicrob AgentsChemother 1997; 41:2016-8.

(J) Diversity among Multidrug-Resistant Enterococci Barbara E. Murray,M.D. Emerg Infect Dis. 2003 September. Available from: URL:http://www.cdc.gov/ncidod/EID/vol4no1/murray.htm

SUMMARY OF THE INVENTION

In a first aspect, the present invention provides a compound of formulaI,

-   -   or pharmaceutically acceptable derivatives thereof, wherein:    -   Ar₁ and Ar₂ are each independently selected from an aromatic or        heterocyclic ring system or partially or fully reduced        derivatives thereof;    -   Q₁ and Q₂ are each independently selected from hydrogen,        C₁-C₁₂alkyl, C₃-C₆cycloalkyl, C₁-C₁₂alkyloxy, nitro, halogen,        hydroxyl, amino, mono or dialkylamino, carboxylic acid or a salt        or ester thereof, sulphonic acid or a salt or ester thereof,        phosphoric acid or a salt or ester thereof, or a nitrogen        containing group such as carboxamide, sulphonamide or        phosphoramide wherein each C₁-C₁₂alkyl, C₁-C₁₂alkyloxy or        C₃-C₆cycloalkyl is optionally substituted with hydroxyl, amino,        carboxylic acid or a salt or ester thereof, sulphonic acid or a        salt or ester thereof, phosphoric acid or a salt or ester        thereof, or a nitrogen containing group such as carboxamide,        sulphonamide or phosphoramide;    -   B is selected from —O—, —S—, —S(O)—, —S(O)₂—, —NH—, and        —N(C₁-C₆alkyl)-;    -   R₁ is selected from hydrogen, C₁-C₁₂alkyl,        C₁-C₆alkylC₃-C₆cycloalkyl, C₁-C₆alkylC₆₋C₁₀aryl, C₂-C₆alkenyl,        C₂-C₆alkynyl, a polyoxyalkylene having from 2 to 6 carbon atoms,        and when B is —S—, —S(O)—, —S(O)₂—, —NH— or —N(C₁-C₆alkyl)- then        R₁ may be hydroxyl;    -   V is a linker group selected from —O—, —O-L-C(O), —O-L-NR₆—,        —C(O), —NR₆—, —S(O)—, —S(O)₂—, —O-L-S(O)—, —S(O)₂-L-C(O)—,        —S(O)₂-L-NR₆—, P(O)₂₋₀—;        -   wherein L is selected from C₁-C₁₂alkyl, C₂-C₈ alkenyl,            C₃-C₆cycloalkyl, polyoxyalkylene having from 2 to 6 carbon            atoms, C₆₋C₁₀aryl and C₁-C₆alkylC₆₋C₁₀aryl and wherein R₆ is            selected from H, C₁-C₁₂alkyl;    -   A₁ and A₂ are the same or different and are basic amino acid        residues;    -   each of S₁, S₂ and S₃ is either present or absent and is an        independently selected amino acid residue;    -   T is present or absent and is selected from —C(O)R₈, —C(O)OR₈,        —OR₈, —NHR₈, NHOR₈, —NH—C₆aryl-CO—R₈, —NH—C₆aryl-CO—NHR₈,        —NH—C₆aryl-CONHOR₈, —NH—C₆aryl-CONHOH, —C(O)NHR₈,        —(NH)—SO₂C₆aryl, —(NH)COR₈;        -   or T forms a carboxylate isostere, optionally substituted            with R₈, which replaces the carboxylic acid group of the            amino acid to which T is connected;        -   wherein R₈ is selected from hydrogen, C₁-C₁₂alkyl,            C₁-C₆alkylC₆₋C₁₀aryl, C₁-C₆alkylC₃-C₆cycloalkyl,            C₂-C₆alkenyl, and C₂-C₆alkynyl; and        -   wherein when T is connected to the C-terminus of an amino            acid residue then the carbonyl group of the amino acid            residue may be reduced to methylene.

In a second aspect, there is provided a compound of formula II,

-   -   or pharmaceutically acceptable derivatives thereof, wherein:    -   Ar₁ and Ar₂ are each independently selected from an aromatic or        heterocyclic ring system or partially or fully reduced        derivatives thereof;

Q₁ and Q₂ are each independently selected from hydrogen, C₁-C₁₂alkyl,C₃-C₆cycloalkyl, C₁-C₁₂alkyloxy, nitro, halogen, hydroxyl, amino, monoor dialkylamino, carboxylic acid or a salt or ester thereof, sulphonicacid or a salt or ester thereof, phosphoric acid or a salt or esterthereof, or a nitrogen containing group such as carboxamide,sulphonamide or phosphoramide wherein each C₁-C₁₂alkyl, C₁-C₁₂alkyloxyor C₃-C₆cycloalkyl is optionally substituted with hydroxyl, amino,carboxylic acid or a salt or ester thereof, sulphonic acid or a salt orester thereof, phosphoric acid or a salt or ester thereof, or a nitrogencontaining group such as carboxamide, sulphonamide or phosphoramide;

-   -   each of V₁ and V₂ is a linker group independently selected from        —O—, —O-L-C(O), —O-L-NR—, —C(O)—, —NR₆—, —S(O)—, —S(O)₂—,        —O-L-S(O)—, —S(O)₂-L-C(O)—, —S(O)₂-L-NR₆—, P(O)₂O—;    -   wherein L is selected from C₁-C₁₂alkyl, C₂-C₈alkenyl,        C₃-C₆cycloalkyl, polyoxyalkylene having from 2 to 6 carbon        atoms, C₆₋C₁₀aryl and C, C₆alkylC₆₋C₁₀aryl and wherein R₆ is        selected from H, C₁-C₁₂alkyl;    -   A₁ and A₂ are the same or different and are basic amino acid        residues;    -   each of S₁, S₂, S₃ and S₄ is either present or absent and is an        independently selected amino acid residue;    -   T₁ is either present or absent and is independently selected    -   from —C(O)R₈, —C(O)OR₈, —OR₈, —NHR₈, —NHOR₈, —NH—C₆aryl-COR₈,        —NH—C₆aryl-CONHR₈, —NH—C₆aryl-CONHOR₈, —NH—C₆aryl-CONHOH,        —C(O)NHR₈, —(NH)—SO₂C₆aryl, —(NH)COR₈;        -   or T₁ forms a carboxylate isostere, optionally substituted            with R₈, which replaces the carboxylic acid group of the            amino acid to which T1 is connected;        -   wherein R₈ is selected from hydrogen, C₁-C₁₂alkyl,            C₁-C₆alkylC₆₋C₁₀aryl, C₁-C₆alkylC₃-C₆cycloalkyl,            C₂-C₆alkenyl, and C₂-C₆alkynyl; and        -   wherein when T1 is connected to the C-terminus of an amino            acid residue then the carbonyl group of the amino acid            residue may be reduced to methylene;    -   T₂ is either present or absent and is independently selected        from —C(O)OR₉, —OR₉, —NHR₉, NHOR₉, —NH—C₆aryl-CO—R₉,        —NH—C₆aryl-CO—NHR₉, —NH—C₆aryl-CONHOR₉, —NH—C₆aryl-CONHOH,        —C(O)NHR₈, —(NH)—SO₂C₆aryl, —(NH)COR₈;        -   or T₂ forms a carboxylate isostere, optionally substituted            with R₉, which replaces the carboxylic acid group of the            amino acid to which T₂ is connected;        -   wherein R₉ is selected from hydrogen, C₁-C₁₂alkyl,            C₁-C₆alkylC₆₋C₁₀aryl, C₁-C₆alkylC₃-C₆cycloalkyl,            C₂-C₆alkenyl, and C₂-C₆alkynyl; and        -   wherein when T₂ is connected to the C-terminus of an amino            acid residue then the carbonyl group of the amino acid            residue may be reduced to methylene.

In a third aspect, there is provided a compound of formula III,

-   -   or pharmaceutically acceptable derivatives thereof, wherein:    -   Ar₁ and Ar₂ are each independently selected from an aromatic or        heterocyclic ring system or partially or fully reduced        derivatives thereof;    -   Q₁ and Q₂ are each independently selected from hydrogen,        C₁-C₁₂alkyl, C₃-C₆cycloalkyl, C₁-C₁₂alkyloxy, nitro, halogen,        hydroxyl, amino, mono or dialkylamino, carboxylic acid or a salt        or ester thereof, sulphonic acid or a salt or ester thereof,        phosphoric acid or a salt or ester thereof, or a nitrogen        containing group such as carboxamide, sulphonamide or        phosphoramide wherein each C₁-C₁₂alkyl, C₁-C₁₂alkyloxy or        C₃-C₆cycloalkyl is optionally substituted with hydroxyl, amino,        carboxylic acid or a salt or ester thereof, sulphonic acid or a        salt or ester thereof, phosphoric acid or a salt or ester        thereof, or a nitrogen containing group such as carboxamide,        sulphonamide or phosphoramide;    -   B is selected from —O—, —S—, —S(O)—, —S(O)₂—, —NH—, and        —N(C₁-C₆alkyl)-;    -   R₁ is selected from hydrogen, C₁-C₁₂alkyl,        C₁-C₆alkylC₃-C₆cycloalkyl, C₁-C₆alkylC₆₋C₁₀aryl, C₂-C₆alkenyl,        C₂-C₆alkynyl, a polyoxyalkylene having from 2 to 6 carbon atoms,        and when B is —S—, —S(O)—, —S(O)₂—, —NH— or —N(C₁-C₆alkyl)- then        R₁ may be hydroxyl;    -   V₁ is a linker group selected from selected from —O—, —O-L-C(O),        —O-L-NR₆—, —C(O)—, —NR₆—, —S(O)—, —S(O)₂—, —O-L-S(O)—,        —S(O)₂-L-C(O)—, —S(O)₂-L-NR₆—, —P(O)₂O—;        -   wherein L is selected from C₁-C₁₂alkyl, C₂-C₈alkenyl,            C₃-C₆cycloalkyl, polyoxyalkylene having from 2 to 6 carbon            atoms, C₆₋C₁₀ aryl and C₁-C₆alkylC₆₋C₁₀aryl and wherein R₆            is selected from H, C₁-C₁₂ alkyl;    -   A₁ is a basic amino acid residue;    -   each of S₁ and S₂ is either present or absent and is an        independently selected amino acid residue;    -   T is present or absent and is selected    -   from —C(O)R₈, —C(O)OR₈, —OR₈, —NHR₈, —NHOR₈, —NH—C₆aryl-COR₈,        —NH—C₆aryl-CONHR₈, —NH—C₆aryl-CONHOR₈, —NH—C₆aryl-CONHOH,        —C(O)NHR₈, —(NH)—SO₂C₆aryl, —(NH)COR₈;        -   or T forms a carboxylate isostere, optionally substituted            with R₈, which replaces the carboxylic acid group of the            amino acid to which T is connected;        -   wherein R₈ is selected from hydrogen, C₁-C₁₂alkyl,            C₁-C₆alkylC₆₋C₁₀aryl, C₁-C₆alkylC₃-C₆cycloalkyl,            C₂-C₆alkenyl, and C₂-C₆alkynyl; and        -   wherein when T is connected to the C-terminus of an amino            acid residue then the carbonyl group of the amino acid            residue may be reduced to methylene.

In a fourth aspect, there is provided a compound of formula IV,

-   -   or pharmaceutically acceptable derivatives thereof, wherein    -   R₁₂ is an alkylaromatic or alkylpolyaromatic group optionally        substituted with —OC₁₋₆alkyl or —OC₂₋₆alkenyl;    -   each B is an independently basic amino acid residue;    -   n=1 or 2;    -   S₁ is present or absent and is an independently selected amino        acid residue;    -   T₁ is selected    -   from —NHR₁₃, —NHOR₁₃, —NH—C₆aryl-COR₁₃, —NH—C₆aryl-CONHR₁₃,        —NH—C₆aryl-CONHOR₁₃, —NH—C₆aryl-CONHOH, —(NH)—SO₂C₆aryl,        —(NH)COR₁₃ or

-   -   or T1 forms a carboxylate isostere, optionally substituted with        R₁₃, which replaces the carboxylic acid group of the amino acid        to which T₁ is connected;    -   wherein R₁₃ is selected from hydrogen, C₁-C₁₂alkyl,        C₁-C₆alkylC₆₋C₁₀aryl, C₁-C₆alkylC₃-C₆cycloalkyl, C₂-C₆alkenyl,        and C₂-C₆alkynyl; and    -   wherein when T₁ is connected to the C-terminus of an amino acid        residue then the carbonyl group of the amino acid residue may be        reduced to methylene;    -   T₂ is selected from —C(O)R₁₄, —C(O)OR₁₄, —OR₁₄, —C(O)NHR₁₄;    -   wherein R₁₄ is selected from hydrogen, C₁-C₁₂alkyl,        C₁-C₆alkylC₆₋C₁₀aryl, C₁-C₆alkylC₃-C₆cycloalkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl, and CH₂-fluorene;    -   wherein the optional substituent of R₁₂ and the side-chain of S₁        may together form a —OC₁₋₆alkylene linking group.

In a fifth aspect, there is a provided a compound of Example 2.

In a sixth aspect, there is provided a composition comprising a compoundaccording to any one of the first to fifth aspects, a salt or apharmaceutically acceptable derivative thereof together with one or morepharmaceutically acceptable carriers or adjuvants.

In a seventh aspect, there is provided a method of treating a bacterialinfection in a mammal comprising administering an effective amount ofcompound according to any one of the first to fifth aspects, a salt or apharmaceutically acceptable derivative thereof.

In an eighth aspect, there is provided a method for treatment orprophylaxis of HIV in a subject comprising administering to said subjectan effective amount of a compound according to any one of the first tofifth aspects, a salt or a pharmaceutically acceptable derivativethereof.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. shows a diagrammatic representation of the antibacterialscreening assay design using a 96-well microtitre plate.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect, the present invention provides a compound of formulaI,

-   -   or pharmaceutically acceptable derivatives thereof, wherein:    -   Ar₁ and Ar₂ are each independently selected from an aromatic or        heterocyclic ring system or partially or fully reduced        derivatives thereof;    -   Q₁ and Q₂ are each independently selected from hydrogen,        C₁-C₁₂alkyl, C₃-C₆cycloalkyl, C₁-C₁₂alkyloxy, nitro, halogen,        hydroxyl, amino, mono or dialkylamino, carboxylic acid or a salt        or ester thereof, sulphonic acid or a salt or ester thereof,        phosphoric acid or a salt or ester thereof, or a nitrogen        containing group such as carboxamide, sulphonamide or        phosphoramide wherein each C₁-C₁₂alkyl, C₁-C₁₂alkyloxy or        C₃-C₆cycloalkyl is optionally substituted with hydroxyl, amino,        carboxylic acid or a salt or ester thereof, sulphonic acid or a        salt or ester thereof, phosphoric acid or a salt or ester        thereof, or a nitrogen containing group such as carboxamide,        sulphonamide or phosphoramide;    -   B is selected from —O—, —S—, —S(O)—, —S(O)₂—, —NH—, and        —N(C₁-C₆alkyl)-;    -   R₁ is selected from hydrogen, C₁-C₁₂alkyl,        C₁-C₆alkylC₃-C₆cycloalkyl, C₁-C₆alkylC₆₋C₁₀aryl, C₂-C₆alkenyl,        C₂-C₆alkynyl, a polyoxyalkylene having from 2 to 6 carbon atoms,        and when B is —S—, —S(O)—, —S(O)₂—, —NH— or —N(C₁-C₆alkyl)- then        R₁ may be hydroxyl;    -   V is a linker group selected from —O—, —O-L-C(O), —O-L-NR₆—,        —C(O)—, —NR₆—, —S(O)—, —S(O)₂—, —O-L-S(O)—, —S(O)₂-L-C(O)—,        —S(O)₂-L-NR₆—, P(O)₂O—;        -   wherein L is selected from C₁-C₁₂alkyl, C₂-C₈ alkenyl,            C₃-C₆cycloalkyl, polyoxyalkylene having from 2 to 6 carbon            atoms, C₆₋C₁₀aryl and C₁-C₆alkylC₆₋C₁₀aryl and wherein R₆ is            selected from H, C₁-C₁₂alkyl;    -   A₁ and A₂ are the same or different and are basic amino acid        residues;    -   each of S₁, S₂ and S₃ is either present or absent and is an        independently selected amino acid residue;    -   T is present or absent and is selected from —C(O)OR₈, —OR₈,        —NHR₈, NHOR₈, —NH—C₆aryl-CO—R₈, —NH—C₆aryl-CO—NHR₈,        —NH—C₆aryl-CONHOR₈, —NH—C₆aryl-CONHOH, —C(O)NHR₈,        —(NH)—SO₂C₆aryl, —(NH)COR₈;        -   or T forms a carboxylate isostere, optionally substituted            with R₈, which replaces the carboxylic acid group of the            amino acid to which T is connected;        -   wherein R₈ is selected from hydrogen, C₁-C₁₂alkyl,            C₁-C₆alkylC₆₋C₁₀aryl, C₁-C₆alkylC₃-C₆cycloalkyl,            C₂-C₆alkenyl, and C₂-C₆alkynyl; and        -   wherein when T is connected to the C-terminus of an amino            acid residue then the carbonyl group of the amino acid            residue may be reduced to methylene.

Preferably, A₁ and A₂ are each independently selected from the groupconsisting of lysine, arginine and ornithine. More preferably A₁ isselected from lysine and ornithine and A₂ is selected from arginine.

Preferably, S₁ and S₂ are absent.

In a preferred embodiment, the compound of formula I is of formula Ia:

wherein Q₁, Q₂, V, S₁, A₁, S₁, A₂, S₃, T, B and R₁ are as defined above.

In a further preferred embodiment, the compound of formula I is offormula Ib:

wherein Q₁, Q₂, V, S₁, A₁, S₁, A₂, S₃, T, B and R₁ are as defined above.

In a second aspect, there is provided a compound of formula II,

-   -   or pharmaceutically acceptable derivatives thereof, wherein:    -   Ar₁ and Ar₂ are each independently selected from an aromatic or        heterocyclic ring system or partially or fully reduced        derivatives thereof;    -   Q₁ and Q₂ are each independently selected from hydrogen,        C₁-C₁₂alkyl, C₃-C₆cycloalkyl, C₁-C₁₂alkyloxy, nitro, halogen,        hydroxyl, amino, mono or dialkylamino, carboxylic acid or a salt        or ester thereof, sulphonic acid or a salt or ester thereof,        phosphoric acid or a salt or ester thereof, or a nitrogen        containing group such as carboxamide, sulphonamide or        phosphoramide wherein each C₁-C₁₂alkyl, C₁-C₁₂alkyloxy or        C₃-C₆cycloalkyl is optionally substituted with hydroxyl, amino,        carboxylic acid or a salt or ester thereof, sulphonic acid or a        salt or ester thereof, phosphoric acid or a salt or ester        thereof, or a nitrogen containing group such as carboxamide,        sulphonamide or phosphoramide;    -   each of V₁ and V₂ is a linker group independently selected from        —O—, —O-L-C(O), —O-L-NR₆—, —C(O)—, —NR₆—, —S(O)—, —S(O)₂—,        —O-L-S(O)—, —S(O)₂-L-C(O)—, —S(O)₂-L-NR₆—, —P(O)₂O—;    -   wherein L is selected from C₁-C₁₂ alkyl, C₂-C₈ alkenyl,        C₃-C₆cycloalkyl, polyoxyalkylene having from 2 to 6 carbon        atoms, C₆₋C₁₀aryl and C₁.C₁₆alkylC₆₋C₁₀aryl and wherein R₆ is        selected from H, C₁-C₁₂alkyl;    -   A₁ and A₂ are the same or different and are basic amino acid        residues;    -   each of S₁, S₂, S₃ and S₄ is either present or absent and is an        independently selected amino acid residue;    -   T₁ is either present or absent and is independently selected    -   from —C(O)OR₈, —OR₈, —NHR₈, —NHOR₈, —NH—C₆aryl-COR₈,        —NH—C₆aryl-CONHR₈, —NH—C₆aryl-CONHOR₈, —NH—C₆aryl-CONHOH,        —C(O)NHR₈, —(NH)—SO₂C₆aryl, —(NH)COR₈;        -   or T1 forms a carboxylate isostere, optionally substituted            with R₈, which replaces the carboxylic acid group of the            amino acid to which T1 is connected;        -   wherein R₈ is selected from hydrogen, C₁-C₁₂alkyl,            C₁-C₆alkylC₆₋C₁₀aryl, C₁-C₆alkylC₃-C₆cycloalkyl,            C₂-C₆alkenyl, and C₂-C₆alkynyl; and        -   wherein when T1 is connected to the C-terminus of an amino            acid residue then the carbonyl group of the amino acid            residue may be reduced to methylene;    -   T₂ is either present or absent and is independently selected        from —C(O)OR₉, —OR₉, —NHR₉, NHOR₉, —NH—C₆aryl-CO—R₉,        —NH—C₆aryl-CO—NHR₉, —NH—C₆aryl-CONHOR₉, —NH—C₆aryl-CONHOH,        —C(O)NHR₈, —(NH)—SO₂C₆aryl, —(NH)COR₈;        -   or T₂ forms a carboxylate isostere, optionally substituted            with R₉, which replaces the carboxylic acid group of the            amino acid to which T₂ is connected;        -   wherein R₉ is selected from hydrogen, C₁-C₁₂alkyl,            C₁-C₆alkylC₆₋C₁₀aryl, C₁-C₆alkylC₃-C₆cycloalkyl,            C₂-C₆alkenyl, and C₂-C₆alkynyl; and        -   wherein when T₂ is connected to the C-terminus of an amino            acid residue then the carbonyl group of the amino acid            residue may be reduced to methylene.

Preferably, A₁ and A₂ are each independently selected from the groupconsisting of lysine, arginine and ornithine.

Preferably, A₁ and A₂ are the same.

Preferably, S₁, S₂, S₃ and S₄ are absent.

In a third aspect, there is provided a compound of formula III,

-   -   or pharmaceutically acceptable derivatives thereof, wherein:    -   Ar₁ and Ar₂ are each independently selected from an aromatic or        heterocyclic ring system or partially or fully reduced        derivatives thereof;    -   Q₁ and Q₂ are each independently selected from hydrogen,        C₁-C₁₂alkyl, C₃-C₆cycloalkyl, C₁-C₁₂alkyloxy, nitro, halogen,        hydroxyl, amino, mono or dialkylamino, carboxylic acid or a salt        or ester thereof, sulphonic acid or a salt or ester thereof,        phosphoric acid or a salt or ester thereof, or a nitrogen        containing group such as carboxamide, sulphonamide or        phosphoramide wherein each C₁-C₁₂alkyl, C₁-C₁₂alkyloxy or        C₃-C₆cycloalkyl is optionally substituted with hydroxyl, amino,        carboxylic acid or a salt or ester thereof, sulphonic acid or a        salt or ester thereof, phosphoric acid or a salt or ester        thereof, or a nitrogen containing group such as carboxamide,        sulphonamide or phosphoramide;    -   B is selected from —O—, —S—, —S(O)—, —S(O)₂—, —NH—, and        —N(C₁-C₆alkyl)-;    -   R₁ is selected from hydrogen, C₁-C₁₂alkyl,        C₁-C₆alkylC₃-C₆cycloalkyl, C₁-C₆alkylC₆₋C₁₀aryl, C₂-C₆alkenyl,        C₂-C₆alkynyl, a polyoxyalkylene having from 2 to 6 carbon atoms,        and when B is —S—, —S(O)—, —S(O)₂—, —NH— or —N(C₁-C₆alkyl)- then        R₁ may be hydroxyl;    -   V₁ is a linker group selected from selected from —O—, —O-L-C(O),        —O-L-NR₆—, —C(O)—    -   —NR₆—, —S(O)—, —S(O)₂—, —O-L-S(O)—, —S(O)₂-L-C(O)—,        —S(O)₂-L-NR₆—, P(O)₂O—        -   wherein L is selected from C₁-C₁₂alkyl, C₂-C₈alkenyl,            C₃-C₆cycloalkyl, polyoxyalkylene having from 2 to 6 carbon            atoms, C₆₋C₁₀ aryl and C₁-C₆alkylC₆₋C₁₀aryl and wherein R₆            is selected from H, C₁-C₁₂ alkyl;    -   A₁ is a is a basic amino acid residue;    -   each of S₁ and S₂ is either present or absent and is an        independently selected amino acid residue;    -   T is present or absent and is selected from —C(O)OR₈, —OR₈,        —NHR₈, —NHOR₈, —NH—C₆aryl-COR₈, —NH—C₆aryl-CONHR₈,        —NH—C₆aryl-CONHOR₈, —NH—C₆aryl-CONHOH, —C(O)NHR₈,        —(NH)—SO₂C₆aryl, —(NH)COR₈;        -   or T forms a carboxylate isostere, optionally substituted            with R₈, which replaces the carboxylic acid group of the            amino acid to which T is connected;        -   wherein R₈ is selected from hydrogen, C₁-C₁₂alkyl,            C₁-C₆alkylC₆₋C₁₀aryl, C₁-C₆alkylC₃-C₆cycloalkyl,            C₂-C₆alkenyl, and C₂-C₆alkynyl; and        -   wherein when T is connected to the C-terminus of an amino            acid residue then the carbonyl group of the amino acid            residue may be reduced to methylene.

Preferably, A₁ is selected from lysine, arginine and ornithine.

In a fourth aspect, there is provided a compound of formula IV,

-   -   or pharmaceutically derivatives thereof, wherein    -   R₁₂ is an alkylaromatic or alkylpolyaromatic group optionally        substituted with —OC₁₋₆alkyl or —OC₂₋₆alkenyl;    -   each B is an independently selected basic amino acid residue;    -   n=1 or 2;    -   S₁ is present or absent and is an independently selected amino        acid residue;    -   T₁ is selected    -   from —NHR₁₃, —NHOR₁₃, —NH—C₆aryl-COR₁₃, —NH—C₆aryl-CONHR₁₃,        —NH—C₆aryl-CONHOR₁₃, —NH—C₆aryl-CONHOH, —(NH)—SO₂C₆aryl,        —(NH)COR₁₃ or

-   -   or T₁ forms a carboxylate isostere, optionally substituted with        R₁₃, which replaces the carboxylic acid group of the amino acid        to which T, is connected;    -   wherein R₁₃ is selected from hydrogen, C₁-C₁₂alkyl,        C₁-C₆alkylC₆₋C₁₀aryl, C₁-C₆alkylC₃-C₆cycloalkyl, C₂-C₆alkenyl,        and C₂-C₆alkynyl; and    -   wherein when T, is connected to the C-terminus of an amino acid        residue then the carbonyl group of the amino acid residue may be        reduced to methylene;    -   T₂ is selected from —C(O)R₁₄, —C(O)OR₁₄, —OR₁₄, —C(O)NBR₁₄;    -   wherein R₁₄ is selected from hydrogen, C₁-C₁₂alkyl,        C₁-C₆alkylC₆₋C₁₀aryl, C₁-C₆alkylC₃-C₆cycloalkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl, and CH₂-fluorene;    -   wherein the optional substituent of R₁₂ and the side-chain of Si        may together form a —OC₁₋₆alkylene linking group.

Preferably, R₁₂ is selected from —CH₂-phenyl-OCH₂CH═CH₂ and—CH₂-phenylanthracene. Preferably, S₁ is selected from allylglycine.Preferably, T₂ is —C(O)CH₃. Preferably, T, is CH₃O—. Preferably, B isarginine or lysine.

In a fifth aspect, there is provided a compound of Example 2.

Preferably the compound of Example 2 is selected from 69, 70, 71, 72,73, 74, 75, 76, 83, 32, 37, 65, 56, 118, 119, 120, 121, 132, 90, 134,135, 136, 137, 139, 140, 141, 159, 160, 163, 164, 78, 81, 88, 87, 89,165, 166, 167, and 168.

It would be understood by the person skilled in the art the peptidechain formed by the combination of the amino acid residues of thecompounds of the present invention could be a peptide or a reversepeptide depending on the nature of the linker group V: for example,where the group V is of the form O-L-C(O)— then the peptide will be apeptide chain with its N-terminus bound to V whereas if the group V isof the form —O-L-NH— then the peptide will be a reverse peptide chainwith its C-terminus bound to V.

As is well known to those skilled in the art, the term carboxylateisostere includes any moiety capable of replacing the carboxylate groupof an amino acid. Suitable carboxylate isosteres include tetrazole (ref:e.g JOC 1992, 57, 202-209; JACS 1998, 110, 5875-5880 or Tet. Lett, 1993,34, 1757-1760.), isoxazole, oxazole and thiazole.

As used herein, the term “halo” or “halogen” refers to fluorine(fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo).

As used herein, the term “alkyl” either used alone, having 1 to 12,preferably 1 to 8, more preferably 1 to 6, carbon atoms, or in compoundterms such as NH(alkyl) or N(alkyl)₂, refers to monovalent straightchain or branched hydrocarbon groups having 1 to 12 carbon atoms,including their stereoisomeric forms if applicable. For example,suitable alkyl groups include, but are not limited to methyl, ethyl,propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl,2-methylbutyl, 3-methylbutyl, n-hexyl, 2-, 3- or 4-methylpentyl,2-ethylbutyl, n-hexyl, and 2-, 3-, 4- or 5-methylpentyl.

As used herein, the term “alkenyl” refers to straight chain or branchedhydrocarbon groups having one or more double bonds between carbon atoms.Suitable alkenyl groups include, but are not limited to ethenyl,propenyl, isopropenyl, butenyl, pentenyl and hexenyl.

The term “alkynyl” as used herein, refers to straight chain or branchedhydrocarbon groups containing one or more triple bonds. Suitable alkynylgroups include, but are not limited to ethynyl, propynyl, butynyl,pentynyl and hexenyl.

The term “cycloalkyl” as used herein, refers to cyclic hydrocarbongroups. Suitable cycloalkyl groups include, but are not limited tocyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term “aryl” as used herein, refers to a C₆₋C₁₀ aromatic hydrocarbongroup, for example phenyl or naphthyl.

The term “heterocycle” when used alone or in compound words includesmonocyclic, polycyclic, fused or conjugated hydrocarbon residues,preferably C₃₋₆, wherein one or more carbon atoms (and whereappropriate, hydrogen atoms attached thereto) are replaced by aheteroatom so as to provide a non-aromatic or aromatic residue. Suitableheteroatoms include, O, N and S. Where two or more carbon atoms arereplaced, this may be by two or more of the same heteroatom or bydifferent heteroatoms. Suitable examples of heterocyclic groups mayinclude pyrrolidinyl, pyrrolinyl, piperidyl, piperazinyl, morpholino,indolinyl, indazolyl, quinolinyl, isoquinolinyl, imidazolidinyl,pyrazolidinyl, thiomorpholino, dioxanyl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydropyrrolyl etc.

Each alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heterocyclyl group maybe optionally substituted with C₁-C₆alkyl, OH, OC₁-C₆alkyl, halo, CN,NO₂, CO₂H, CO₂C₁-C₆alkyl, CONH₂, CONH(C₁-C₆alkyl), CON(C₁-C₆alkyl)₂,trifluoromethyl, C₆aryl, C₃-C₆cycloalkyl, hetrocyclyl, NH₂,NH(C₁-C₆alkyl) or N(C₁-C₆alkyl)₂. For example, an optionally substitutedaryl group may be 4-methylphenyl or 4-hydroxyphenyl group, and anoptionally substituted alkyl group may be 2-hydroxyethyl,trifluoromethyl, or difluoromethyl. Further, methyl substituents(C₁alkyl) may be substituted with an optionally substituted aryl to forma benzyl substituent.

As used herein, the term “amino acid residue” refers to an amino acidwhich is bound by means of amide bonds or suitable replacements thereofto one or more of the linker group V, other amino acid residues and theterminal group T. The amino acid may be an α-amino acid or a β-aminoacid. A suitable replacement for the amide bond can be any replacementthat is known in the art as it is well known that where two amino acidsor a combination of natural and unnatural amino acids are joinedtogether to form an amide bond between them the bond can be replaced bya suitable link, which may be called a peptoid (discussion of this maybe found in P M Fischer ‘The design, synthesis and application ofstereochemical and directional peptide isosteres a critical review’Curr. Protein and Peptide Science, 2003, 4(5), 339-356 and referencestherein). Examples of suitable replacements include, but are not limitedto:

-   -   reduced amide: amino methylene: CH₂NH; (Szelke, M., Leckie, B.;        Hallet A., Jones, D. M., Sueiras, J.; Atrash. B.; Lever, A.,        Nature, 19821982, 299, 555-557.; Ambo A, Adachi T, Sasaki Y.        Synthesis and opioid activities of [D-Leu-8]Dynorphin(1-8)        analogs containing a reduced peptide bond, psi(CH₂—NH). Chem        Pharm Bull (Tokyo). 1995, 43(9), 1547-50)    -   ether bond: CH₂O; (Hedenstrom M, Yuan Z, Brickmann K, Carlsson        J, Ekholm K, Johansson B, Kreutz E, Nilsson A, Sethson I,        Kihlberg j. Conformations and receptor activity of desmopressin        analogues, which contain gamma-turn mimetics or a psi[CH(₂)O]        isostere. J Med Chem. 2002, 45(12), 2501-11)    -   hydroxy ethylene CHOHCH₂— and ketomethylene COCH₂; (Harbeson S        L, Rich D H. Inhibition of aminopeptidases by peptides        containing ketomethylene and hydroxyethylene amide bond        replacements. J Med Chem. 1989, 32(6), 1378-92)    -   urea NHCONH; (Dales N A, Bohacek R S, Satyshur K A, Rich D H.        Design and synthesis of unsymmetrical peptidyl urea inhibitors        of aspartic peptidases Org Lett. 2001, 3(15), 2313-6)

The amino acid may be a L- or D-isomer and may have a naturallyoccurring side chain or a non-naturally occurring side chain. The aminoacid may also be further substituted in the α-position or the β-positionwith a group selected from —C₁-C₁₂alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl,—(CH₂)_(n)COR_(a), —(CH₂)_(n)R_(b), —PO₃H, —(CH₂)_(n)heterocyclyl or—(CH₂)_(n)aryl where R_(a) is —OH, —NH₂, —NHC₁-C₆alkyl,—OC₁-C₁₂alkylC₁-C₁₂alkyl and R_(b) is —OH, —SH, —SC₁-C₆alkyl,—OC₁-C₁₂alkyl, —C₃-C₆cycloalkyl, —C₃-C₆cycloalkenyl, —NH₂, —NHC₁-C₆alkylor —NHC(C═NH)NH₂, n is 0 or an integer from 1 to 6 and where each alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl groupmay be substituted with one or more groups selected from —OH, —NH₂,—NHC₁-C₆alkyl, —OC₁-C₁₂alkyl, —SH, —SC₁-C₆alkyl, —CO₂H, —CO₂C₁-C₆alkyl,—CONH₂ or —CONHC₁-C₆alkyl.

The term “α-amino acid” as used herein, refers to a compound having anamino group and a carboxyl group in which the amino group and thecarboxyl group are separated by a single carbon atom, the α-carbon atom.An α-amino acid includes naturally occurring and non-naturally occurringL-amino acids and their D-isomers and derivatives thereof such as saltsor derivatives where functional groups are protected by suitableprotecting groups. The α-amino acid may also be further substituted inthe α-position with a group selected from —C₁-C₁₂alkyl, —C₂-C₁₀alkenyl,—C₂-C₁₂alkynyl, —(CH₂)_(n)COR₁, —(CH₂)_(n)R₂, —PO₃H,—(CH₂)_(n)heterocyclyl or —(CH₂)_(n)aryl where R₁ is —OH, —NH₂,—NHC₁-C₁₂alkyl, —OC₁-C₁₂alkyl or C₁-C₁₂alkyl and R₂ is —OH, —SH,—SC₁-C₆alkyl, —OC₁-C₁₂alkyl, —C₃-C₆cycloalkylC₃-C₆cycloalkenyl,OC₁-C₁₂alkyl, —NH₂, —NHC₁-C₃alkyl or —NHC(C═NH)NH₂, n is 0 or an integerfrom 1 to 10 and where each alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl or heterocyclyl group may be substituted with one ormore groups selected from —OH, —NH₂, —NHC₁-C₆alkyl, —OC₁-C₁₂alkyl, —SH,—SC₁-C₆alkyl, —CO₂H, —CO₂C₁-C₆alkyl, —CONH₂ or —CONHC₁-C₆alkyl.

As used herein, the term “β-amino acid” refers to an amino acid thatdiffers from an α-amino acid in that there are two (2) carbon atomsseparating the carboxyl terminus and the amino terminus. As such,β-amino acids with a specific side chain can exist as the R or Senantiomers at either of the α (C2) carbon or the β (C3) carbon,resulting in a total of 4 possible isomers for any given side chain. Theside chains may be the same as those of naturally occurring α-aminoacids or may be the side chains of non-naturally occurring amino acids.

Furthermore, the β-amino acids may have mono-, di-, tri- ortetra-substitution at the C2 and C3 carbon atoms. Mono-substitution maybe at the C2 or C3 carbon atom. Di-substitution includes twosubstituents at the C2 carbon atom, two substituents at the C3 carbonatom or one substituent at each of the C2 and C3 carbon atoms.Tri-substitution includes two substituents at the C2 carbon atom and onesubstituent at the C3 carbon atom or two substituents at the C3 carbonatom and one substituent at the C2 carbon atom. Tetra-substitutionprovides for two substituents at the C2 carbon atom and two substituentsat the C3 carbon atom. Suitable substituents include —C₁-C₁₂alkyl,—C₂-C₆alkenyl, —C₂-C₆alkynyl, —(CH₂)_(n)COR_(a), —(CH₂)_(n)R_(b), —PO₃H,—(CH₂)_(n)heterocyclyl or —(CH₂)_(n)aryl where R_(a) is —OH, —NH₂,—NHCl—C₆alkyl, —OC₁-C₁₂alkyl or —C₁-C₁₂alkyl and R_(b) is —OH, —SH,—SC₁-C₆alkyl, —OC₁-C₁₂alkyl, —C₃-C₆cycloalkyl, —C₃-C₆cycloalkenyl, —NH₂,—NHC₁-C₆alkyl or —NHC(C═NH)NH₂, n is 0 or an integer from 1 to 6 andwhere each alkyl, alkenyl, alkynyl cycloalkyl, cycloalkenyl, aryl orheterocyclyl group may be substituted with one or more groups selectedfrom —OH, —NH₂, —NHC₁-C₆alkyl, —OC₁-C₁₂alkyl, —SH, —SC₁-C₆alkyl, —CO₂H,—CO₂C₁-C₆alkyl, —CONH₂ or —CONHC₁-C₆alkyl.

The term “non-naturally occurring amino acid” as used herein, refers toamino acids having a side chain that does not occur in the naturallyoccurring L-α-amino acids. Examples of non-natural amino acids andderivatives include, but are not limited to, use of norleucine, 4-aminobutyric acid, 4-amino-3-hydroxy-5-phenylpentanoic acid, 6-aminohexanoicacid, t-butylglycine, norvaline, phenylglycine, ornithine, sarcosine,4-amino-3-hydroxy-6-methylheptanoic acid, 2-thienyl alanine and/orD-isomers of amino acids.

The term “basic amino acid” includes any amino acid having a side chainthat can act as a base and generally includes amino acids having a sidechain bearing one or more nitrogen atoms. Included within the definitionare the naturally occurring basic L-amino acids lysine, arginine, andhistidine and their D-isomers. Further included are the L- and D-formsof ornithine; 2-, 3- and 4-amidinophenylglycine; 2, 3, and 4amidinophenylalanine; 2-, 3- and 4-guanidinophenylglycine;pyridylalanine; cysteic- and homocysteic acid-S-(aminoiminomethyl)amides; and amidinopiperidinylalanine. Preferably, the side-chaincomprises an amino group (NH₂) or an amino group substituted on thenitrogen atom with up to two substituents. Examples of optionalsubstituents include C₁-C₁₂alkyl, C₃-C₇cycloalkyl, C₆₋C₁₀aryl, benzyl,and suitable nitrogen protecting groups (see “Protective Groups inOrganic Synthesis” Theodora Greene and Peter Wuts, third edition, WileyInterscience, 1999). Preferably, the amino group is capable of carryinga positive charge at physiological pH. In a preferred form of theinvention, the side chain comprises a substituent selected from a groupconsisting

of: —N(R₁₀)₂, —N(R₁₀)—COR₁₁, —NR₁₀C(═NR₁₀)N(R₁₀)₂, —C(═NR₁₀)N(R₁₀)₂,—NR₁₀C(═O)N(R₁₀)₂, —N═NC(═NR₁₀)N(R₁₀)₂, NR₁₀NR₁₀C(═O)NHN(R₁₀)₂,—NR₁₀CC═NHN(R₁₀)₂ wherein each R₁₀ is independently selected fromhydrogen and C₁-C₆alkyl and R11 is selected from hydrogen, hydroxy,C₁-C₁₂alkyl, C₁-C₆alkoxy and NR₁₀; and 3-8-membered N-containingheterocyclic group such as piperidinyl, pyrollodinyl, imidazolinyl,pyrazolidinyl or piperazinyl, wherein the 3-8-membered N-containingheterocyclic group can be attached via a nitrogen or carbon atom.Preferred substituents include optionally substituted guanidine[—NHC(═NH)NH₂], amidino [—C(═NH)NH₂], ureido [—NHC(═O)NH₂], carbazono[—N═NC(═)NHNH₂], carbazido [—NHNHC(═O)NHNH₂] and semicarbazido[—NHC(═O)NHNH₂] and amino ([NH₂].

The compounds of the present invention include binaphthyl derivatives.Substituted binaphthyl derivatives are chiral compounds. The presentinvention encompassed both enantiomeric forms. Preferably, when thecompound of the present invention is a 2,2′-binapthyl derivative thenthe binapthyl group is in the S configuration.

The term “pharmaceutically acceptable derivative” may include anypharmaceutically acceptable salt, hydrate or prodrug, or any othercompound which upon administration to a subject, is capable of providing(directly or indirectly) a compound of the present invention or apharmaceutically active metabolite or residue thereof.

The salts of the compound of formulae (I) to (IV) are preferablypharmaceutically acceptable, but it will be appreciated thatnon-pharmaceutically acceptable salts also fall within the scope of thepresent invention, since these are useful as intermediates in thepreparation of pharmaceutically acceptable salts.

Suitable pharmaceutically acceptable salts include, but are not limitedto, salts of pharmaceutically acceptable inorganic acids such ashydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic,and hydrobromic acids, or salts of pharmaceutically acceptable organicacids such as acetic, propionic, butyric, tartaric, maleic,hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic,succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic,benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic,stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic andvaleric acids. Base salts include, but are not limited to, those formedwith pharmaceutically acceptable cations, such as sodium, potassium,lithium, calcium, magnesium, zinc, ammonium, alkylammonium such as saltsformed from triethylamine, alkoxyammonium such as those formed withethanolamine and salts formed from ethylenediamine, choline or aminoacids such as arginine, lysine or histidine. General information ontypes of pharmaceutically acceptable salts and their formation is knownto those skilled in the art and is as described in general texts such as“Handbook of Pharmaceutical salts” P. H. Stahl, C. G. Wermuth, 1^(st)edition, 2002, Wiley-VCH.

Basic nitrogen-containing groups may be quarternised with such agents aslower alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides,bromides and iodides; dialkyl sulfates like dimethyl and diethylsulfate; and others.

The term “prodrug” is used in its broadest sense and encompasses thosederivatives that are converted in vivo to the compounds of theinvention. Such derivatives would readily occur to those skilled in theart, and include, for example, compounds in which a free hydroxy groupis converted into a group, such as an ester, carbonate or carbamate,which is capable of being converted in vivo back to a hydroxy group. Aprodrug may include modifications of one or more of the functionalgroups of a compound of formula (I). In particular, compounds of formulaI having free amino, amido, hydroxy or carboxylic groups can beconverted into prodrugs. Prodrugs include compounds wherein an aminoacid residue, or a polypeptide chain of two or more (eg, two, three orfour) amino acid residues which are covalently joined through peptidebonds to free amino, hydroxy and carboxylic acid groups of compounds offormula I. The amino acid residues include the 20 naturally occurringamino acids commonly designated by three letter symbols and alsoinclude, 4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvlin, beta-alanine, gamma-aminobutyric acid,citrulline, homocysteine, homoserine, ornithine and methioine sulfone.Prodrugs also include compounds wherein carbonates, carbamates, amidesand alkyl esters which are covalently bonded to the above substituentsof formula I through the carbonyl carbon prodrug sidechain. Prodrugsalso include phosphate derivatives of compounds of the present invention(such as acids, salts of acids, or esters) joined through aphosphorus-oxygen bond to a free hydroxyl of the compound I.

It will also be recognised that the compounds of the first to fifthaspects may possess asymmetric centres and are therefore capable ofexisting in more than one stereoisomeric form. The invention thus alsorelates to compounds in substantially pure isomeric form at one or moreasymmetric centres e.g., greater than about 90% ee, such as about 95% or97% ee or greater than 99% ee, as well as mixtures, including racemicmixtures, thereof. Such isomers may be prepared by asymmetric synthesis,for example using chiral intermediates, or by chiral resolution.

In a sixth aspect, there is provided a composition comprising a compoundaccording to any one of the first to fifth aspects, a salt or apharmaceutically acceptable derivative thereof together with one or morepharmaceutically acceptable carriers or adjuvants.

The compositions of the present invention may contain other therapeuticagents as described below, and may be formulated, for example, byemploying conventional solid or liquid vehicles or diluents, as well aspharmaceutical additives of a type appropriate to the mode of desiredadministration (for example, excipients, binders, preservatives,stabilizers, flavors, etc.) according to techniques such as those wellknown in the art of pharmaceutical formulation.

In a seventh aspect, there is provided a method of treating a bacterialinfection in a mammal comprising administering an effective amount ofcompound according to any one of the first to fifth aspects, a salt or apharmaceutically acceptable derivative thereof.

Yet another aspect of the present invention provides a use of a compoundof the first to fifth aspects in the preparation of a medicament fortreating or preventing bacterial infection. They are particularly usefulfor treating infections caused by Gram positive bacteria such asenterococcus faecium, Staphylococcus aureus, Staphylococcus epidermis,Klebsiella pneumoniae, Streptococcus pneumoniae, includingmulti-resistant strains such as vancomycin resistant Staphylococcusaureus and methicillin-resistant Staphylococcus aureus.

Accordingly the invention provides the use of a compound of the first tofifth aspects for treatment or prophylaxis of bacterial infections andprovides method comprising of administering an suitable amount of acompound according to one of the first to fifth aspects.

Suitable dosages may lie within the range of about 0.1 ng per kg of bodyweight to 1 g per kg of body weight per dosage. The dosage is preferablyin the range of 1 μg to 1 g per kg of body weight per dosage, such as isin the range of 1 mg to 1 g per kg of body weight per dosage. In oneembodiment, the dosage is in the range of 1 mg to 500 mg per kg of bodyweight per dosage. In another embodiment, the dosage is in the range of1 mg to 250 mg per kg of body weight per dosage. In yet anotherpreferred embodiment, the dosage is in the range of 1 mg to 100 mg perkg of body weight per dosage, such as up to 50 mg per kg of body weightper dosage. In yet another embodiment, the dosage is in the range of 1μg to 1 mg per kg of body weight per dosage.

Suitable dosage amounts and dosing regimens can be determined by theattending physician and may depend on the severity of the condition aswell as the general age, health and weight of the subject.

The active ingredient may be administered in a single dose or a seriesof doses. While it is possible for the active ingredient to beadministered alone, it is preferable to present it as a composition,preferably as a pharmaceutical formulation.

This invention thus further provides pharmaceutical formulationcomprising a compound of the invention or a pharmaceutically acceptablesalt or derivative thereof together with one or more pharmaceuticallyacceptable carriers thereof and, optionally, other therapeutic and/orprophylactic ingredients. The carriers(s) must be “acceptable’ in thesense of being compatible with other ingredients of the formulation andnot deleterious to the recipient thereof.

Pharmaceutical formulations include those for oral, rectal, nasal,topical (including buccal and sub-lingual), vaginal or parenteral(including intramuscular, sub-cutaneous and intravenous) administrationor in a form suitable for administration by inhalation or insufflation.The compounds of the invention, together with a conventional adjuvant,carrier or diluent, may thus be placed into the form of pharmaceuticalcompositions and unit dosages thereof, and in such form may be employedas solids, such as tablets or filled capsules, or liquids as solutions,suspensions, emulsions, elixirs or capsules filled with the same, allfor oral use, in the form of suppositories for rectal administration; orin the form of sterile injectable solutions for parenteral (includingsubcutaneous) use.

In addition to primates, such as humans, a variety of other mammals canbe treated according to the method of the present invention. Forinstance, mammals including, but not limited to, cows, sheep, goats,horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine,canine, feline, rodent or murine species can be treated. However, themethod can also be practiced in other species, such as avian species(e.g., chickens).

The subjects treated in the above method are mammals, including, but notlimited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats orother bovine, ovine, equine, canine, feline, rodent or murine species,and preferably a human being, male or female.

As used herein, the term “effective amount” relates to an amount ofcompound which, when administered according to a desired dosing regimen,provides the desired treatment of the bacterial infection or therapeuticactivity, or disease prevention. Dosing may occur at intervals ofminutes, hours, days, weeks, months or years or continuously over anyone of these periods. A therapeutic, or treatment, effective amount isan amount of the compound which, when administered according to adesired dosing regimen, is sufficient to at least partially attain thedesired therapeutic effect, or delay the onset of, or inhibit theprogression of or halt or partially or fully reverse the onset orprogression of the bacterial infection. A prevention effective amount isan amount of compound which when administered according to the desireddosing regimen is sufficient to at least partially prevent or delay theonset of a particular disease or condition.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The terms “administration of” and or “administering a” compound shouldbe understood to mean providing a compound of the invention to theindividual in need of treatment.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active object compound is included inan amount sufficient to produce the desired effect upon the process orcondition of diseases. As used herein, the term “composition” isintended to encompass a product comprising the specified ingredients inthe specified amounts, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The pharmaceutical composition and method of the present invention mayfurther comprise other therapeutically active compounds which areusually applied in the treatment of the above mentioned pathologicalconditions. Selection of the appropriate agents for use in combinationtherapy may be made by one of ordinary skill in the art, according toconventional pharmaceutical principles. The combination of therapeuticagents may act synergistically to effect the treatment or prevention ofthe various disorders described above. Using this approach, one may beable to achieve therapeutic efficacy with lower dosages of each agent,thus reducing the potential for adverse side effects.

When other therapeutic agents are employed in combination with thecompounds of the present invention they may be used for example inamounts as noted in the Physician Desk Reference (PDR) or as otherwisedetermined by one of ordinary skill in the art.

In addition to the antibacterial properties of compounds of the presentinvention, the present inventors have also found that compounds of thepresent invention are also effective in treating HIV. Accordingly, in aneighth aspect the present invention provides a method for treatment orprophylaxis of HIV in a subject comprising administering to said subjectan effective amount of a compound according to any one of the first tofourth aspects, a salt or a pharmaceutically acceptable derivativethereof.

Preferably, the compound is selected from one or more of the followingcompounds of Example 2: 78, 81, 88, 89, 165, 166, 167, 168, 83, 119,164, 163, 158.

In order that the nature of the present invention may be more clearlyunderstood, preferred forms thereof will now be described with referenceto the following non-limiting examples.

EXPERIMENTAL

Compounds of Formulae (I) to (III) may be prepared using the methodsdepicted or described herein or known in the art for the preparation ofcompounds of analogous structure. It will be understood that minormodifications to methods described herein or known in the art may berequired to synthesise particular compounds of Formula (I). Generalsynthetic procedures applicable to the synthesis of compounds may befound in standard references such as Comprehensive OrganicTransformations, R. C. Larock, 1989, VCH Publishers, Advanced OrganicChemistry, J. March, 4th edition, 1992, Wiley InterScience, Amino Acidand Peptide Synthesis, J. Jones, (Oxford Chemistry Primers) 2^(nd)edition 2002, Oxford university press, The practice of peptidesynthesis, 2003, 2nd edition, M. Bodansky and A. Bodansky,Springer-Verlag, New York and references therein. It will also berecognised that certain reactive groups may require protection anddeprotection during the synthetic process. Suitable protecting anddeprotecting methods for reactive functional groups are known in the artfor example in Protective Groups in Organic Synthesis, T. W. Greene & P.Wutz, John Wiley & Son, 3^(rd) Edition, 1999.

Compounds of formula (I) as described above, may be prepared by reactinga compound of formula (A):

wherein X is OH or an activating group; with a compound of formula (B)under appropriate conditions.

wherein B, R₁, Ar₁, Ar₂, V, Q₁, Q₂, S₁, A₁, S₂, A₂, S₃, T are as definedin formula (I).

Conveniently the reaction between compounds formulae (A) and (B) isbased upon forming an amide bond and may be conducted using approachesroutinely used in peptide synthesis. For example, the coupling reactionof an amine with a carboxylic acid (X═OH) or an activated carbonylcarbon such as an acyl chloride, acyl azide, acyl-succinimide or ananhydride (X═Cl, N3, O-succinimde, OC(O)R).

Compounds of the formula (A) may be conveniently prepared from anaromatic or heteroaromatic ring system carrying any of;

desired substituents

functional groups which may be converted into desired substituents usingconventional approaches known to those skilled in the art; or

appropriately activated positions on the nucleus of the ring system suchthat desired substituents may be placed on the ring system usingconventional approaches known to those skilled in the art.

In addition the ring system Ar₁—Ar₂ includes a position that may beconverted into the group BR1. This position may be a functional group ormay be an appropriately activated position on the ring to allowconversion into functional groups using conventional approaches known tothose skilled in the art. For example functional groups includehydroxyl, amino and suitably protected derivatives of these. Examples ofsuitably activated positions include those which may be alkylated oracylated such as phenoxide.

The compound of formula (B) can be prepared using any suitable approachreadily ascertainable to those skilled in the art. Preferably compound(B) can be formed by reactions of suitably protected amino acids in asuitable sequence. In one preferred approach this is based uponformation of amide bonds and may be conducted using approaches routinelyused in peptide synthesis, for example, the reaction of an amine with anappropriately activated carbonyl group. Preferably compound (B) may havea protecting group on the amino terminus of S1 or S2 which is removedonce the group S1A1S2A2S3T has been formed to allow coupling of S1 or A1to V of compound (A). Those skilled in the art can readily determine theappropriate methodology to build the desired group (B).

Where appropriate, protecting groups may be used to mask certainpositions on the compounds of formulae (A) and (B) so as to avoid orlimit unwanted side reactions.

Suitable aromatic or heteraromatic ring systems may be commerciallyavailable or be readily prepared from commercially available ringsystems or ring system precursors.

The compounds of the present invention may be prepared according to thegeneral procedure of Scheme 1. Although this process is illustratedusing specific reagents and compounds, it will be appreciated by one ofskill in the art that suitable analogous reagents may be used to prepareanalogous products, as depicted, for example, in scheme 1.

As would be understood by persons skilled in the art compounds offormulae II and III can be prepared by similar methods (afterappropriate modification) to those used to produce compounds of formulaI.

Example 1 Preparation and Biological Activity of Compounds According tothe Present Invention

General Synthetic Procedures

Protocol 1: Peptide Coupling

To a stirred solution of an acid (1 equiv.) and an amine (1 equiv.) indry acetonitrile or DMF (5-10 mls) was added EDCI (1.2 equiv.) and HObt(1.2 equiv.). If the amine was a HCl salt then 1 equivalent of DIPEA wasalso added. The reaction mixture was stirred overnight before thesolvent was removed and the resultant residue subjected to flash silicagel column chromatography (normally using 2% MeOH/DCM as the eluant) toafford the desired compound

Protocol 2: N-Fmoc Deprotection

To a stirring solution of the Fmoc-protected peptide in dry acetonitrile(5-10 mls) was added piperidine (0.1 ml). The resultant solution wasthen stirred at room temperature for 3 hours. The solvent was thenremoved and the resultant residue subjected to flash silica gelchromatography using a short column (using 2% MeOH/DCM then 5% MeOH/DCMupon removal of Fmoc byproducts) to afford the desired compound.

Protocol 3: N-Boc & PMC/PBF Deprotection

To a stirring solution of the protected peptide in DCM (2 mls) was addedTFA (2 mls). The reaction mixture was stirred at room temperature forthree hours before the solvent was removed. After triturating twice morewith DCM (2 mls), the residue was taken up in DCM (2 ml) and treatedwith a HCl/ether solution (2 ml, 1M), stirred for a minute andevaporated to dryness. This treatment with HCl was repeated twice more.For BOC-deprotection this is the final step, for PMC/PBF-deprotectionthe following is completed. The residue is taken up in DCM (or dry MeOHif insoluble in DCM), precipitated by the addition of ether and thesolid collected by centrifugation. This step is repeated once more toremove the protecting group byproduct. The resultant solid is then driedto yield the desired compound as its hydrochloride salt.

Protocol 4

To a stirring solution of the acid, alcohol, and triphenylphosphine inTHF at 0° C. under a nitrogen atmosphere was added DIAD dropwise. Thesolution was allowed to warm to room temperature and stirred overnight.The solvent was then removed in vacuo and the resulting residue purifiedby flash column chromatography over silica to yield the desired product.

Protecting Groups

General Notes

Melting point determinations were carried out on a Gallenkamp meltingpoint apparatus. Chemical ionization (CI) and electron impact (EI) massspectra were obtained on a Shimadzu QP-5000 mass spectrometer by adirect insertion technique with an electron beam energy of 70 eV.Electrospray (ES) m/z mass spectra were obtained on a VG Autospecspectrometer. High-resolution mass spectra (HRMS) were determined on amicromass QT of 2 spectrometer using polyethylene glycol orpolypropylene glycol as the internal standard. The m/z values are statedwith their peak intensity as a percentage in parentheses. Proton andcarbon nuclear magnetic resonance (NMR) spectra were obtained asspecified on a Varian Mercury 300 MHz or Varian Inova 500 MHzspectrometer. Spectra were recorded in the specified deuterated solvent,and referenced to the residual non-deuterated solvent signal. Chemicalshifts (5) in ppm were measured relative to the internal standard.Multiplet (m) signals are reported from the centre of the peak.Analytical thin layer chromatography (TLC) was carried out on Mercksilica gel 60 F₂₅₄ pre-coated aluminium plates with a thickness of 0.2mm. All column chromatography was performed under ‘flash’ conditions onMerck silica gel 60 (230-400 mesh). Chromatography solvent mixtures weremeasured by volume. All compounds were judged to be of greater than 95%purity based upon ¹H NMR and TLC analysis. Starting materials andreagents were purchased from Sigma-Aldrich Pty Ltd or Auspep Pty Ltd andwere used as received.

Compounds of Formula ISynthesis of Compound 1

To a solution of 1,1′-binaphth-2,2′-diol (1 g, 3.49 mmol) in dry acetone(100 ml) was added anhydrous potassium carbonate (5 g). A solution of1-bromo-3-methylbutane (0.52 ml, 4.19 mmol) in acetone (30 ml) was addeddropwise over a 90 min period. The mixture was then heated at reflux for3 hrs and left to sit overnight before being cooled and filtered. Thesolid residue was then washed twice more with acetone (10 ml) before thecombined organic extracts were evaporated to dryness to yield a honeycoloured oil. Subsequent flash column chromatography with 1:1 DCM/Hexaneas the eluant affords the desired product 1(i) as a yellow oil (705 mg,57%). R_(f)=0.64 (1:1 hexane/DCM). Starting diol was also recovered (357mg, 36%) indicating the reaction had not gone to completion.

¹H NMR (300 MHz, CDCl₃) δ 0.61, d, J=6.5 Hz, 3H, 0.65, d, J=6.5 Hz, 3H,1.32, m, 3H, 3.98, m, 2H, 4.95, s, OH; 7.04, dist d, J=7.8 Hz, 1H, 7.25,m, 7H, 7.42, d, J=9.1 Hz, 1H, 7.84, d, J=7.8 Hz, 1H, 7.87, d, J=8.7 Hz,1H, 7.99, d, J=9.0, Hz, 1H.

To 1(i) (532 mg, 1.49 mmol) in dry MeOH (25 ml) was added potassiumcarbonate (2.06 g, 14.9 mmol) and bromoacetic acid (1.03 g, 7.45 mmol).The resultant solution was then heated at reflux for 8 hrs over whichtime a white ppte had fallen out of solution. The reaction mixture wasthen evaporated to dryness and the residue dissolved in water (50 ml).This was then washed with ether (3×30 ml) before the aqueous layer wasacidified with 3M HCl. This acidified solution was then extracted withDCM (3×30 ml) to yield a yellow solution. This yellow solution was thendried (MgSO₄) and evaporated to dryness to yield the product 1(ii) as ayellow oil (325 mg, 53%). Starting material was also recovered (135 mg,25%) indicating the reaction had not gone to completion.

¹H NMR (300 MHz, CDCl₃) δ 0.54, d, J=6.5 Hz, 3H, 0.64, d, J=6.5 Hz, 3H,1.19, m, 1H, 1.30, m, 2H, 3.94, m, 1H, 4.13, m, 1H, 4.57, ABq, J=16.8Hz, 1H, 4.69, ABq, J=16.8 Hz, 1H, 7.26, m, 4H, 7.37, m, 3H, 7.48, d,J=8.8 Hz, 1H, 7.90, d, J=8.2 Hz, 2H, 7.97, d, J=8.8 Hz, 1H, 8.00, d,J=8.8, Hz, 1H, 8.06, br s, COOH. MS (EI +ve) 414 (100%) [M+H]⁺.

This compound was prepared via Protocol 1, using BOC-(L)-leu-OH (600 mg,2.59 mmol) and BzOH (0.41 ml, 4.0 mmol) to yield the desired product1(iii) as an off white solid (512 mg, 62%). R_(f)=0.78 (5% MeOH/DCM),staining with Mo dip.

¹H NMR (300 MHz, CDCl₃) δ 0.91, d, J=6.5 Hz, 6H, 1.44, m, 2H, 1.45, s,9H, 1.66, m, 1H, 4.36, m, 1H, 5.08, ABq, J=12.3 Hz, 1H, 5.17, ABq,J=12.3 Hz, 1H, 5.27, d, J=8.4 Hz, NH; 7.31, m, 5H. MS (ES +ve) m/z 322(100%) [M+H]⁺.

To 1(iii) (510 mg, 1.59 mmol) dissolved in DCM (2 ml) was added TFA (2ml) and the resulting solution stirred at room temperature for 1 hr.Ethyl acetate (15 ml) was then added and the solution washed with sat.sodium bicarbonate solution until the washings were basic. The organiclayer was then dried (MgSO₄) and evaporated to dryness to yield thedesired product 1(iv) as a colourless oil (172 mg, 49%). R_(f)=0.37 (5%MeOH/DCM), staining with Mo dip.

¹H NMR (300 MHz, CDCl₃) δ 0.88, d, J=6.4 Hz, 3H, 0.90, d, J=6.4 Hz, 3H,1.43, m, 2H, 1.54, m, 1H, 1.72, m, 1H, 1.74, m, NH₂; 3.48, m, 1H, 5.12,s, 2H, 7.32, m, 5H. MS (ES +ve) m/z 222 (100%) [M+H]⁺.

This compound was prepared via Protocol 1 using 1(iv) (160 mg, 0.723mmol) and Fmoc-(D)-arg(Pmc)-OH (662.8 mg, 1.00 mmol) to yield thedesired product 1(v) as an off white solid (460 mg, 73%).

¹H NMR (300 MHz, CDCl₃) δ 0.81, m, 6H, 1.21, s, 6H, 1.58, m, 5H, 1.67,m, 3H, 1.85, m, 1H, 2.04, s, 3H, 2.49, m, 2H, 2.54, s, 3H, 2.58, s, 3H,3.21, m, 2H, 4.04, m, 1H, 4.23, m, 3H, 4.52, m, 1H, 5.02, ABq, J=12.3Hz, 1H, 5.08, ABq, J=12.3 Hz, 1H, 6.22, br s, NH; 6.36, bs, NH; 7.25, m,9H, 7.50, d, J=7.3 Hz, 2H, 7.69, d, J=7.3 Hz, 2H. MS (ES +ve) m/z 888(100%) [M+Na]⁺; 866 (10) [M+H]⁺.

This compound was prepared via Protocol 2, using 1(v) (450 mg, 0.520mmol) to yield the desired product 1(vi) as an off white solid (244 mg,73%). R_(f)=0.07 (5% MeOH/DCM).

¹H NMR (300 MHz, CDCl₃) δ 0.88, m, 6H, 1.28, s, 6H, 1.57, m, 5H, 1.77,m, 2H, 1.86, m, 2H, 2.08, s, 3H, 2.54, s, 3H, 2.58, s, 3H, 2.60, m, 2H,3.14, m, 2H, 3.38, m, 1H, 4.51, m, 1H, 5.05, ABq, J=12.3 Hz, 1H, 5.13,ABq, J=12.3 Hz, 1H, 6.33, br s, NH; 6.38, br s, NH; 7.29, m, 5H, 7.78,d, J=7.6 Hz, NH. MS (ES +ve) m/z 644 (100%) [M+H]⁺.

This compound was prepared via Protocol 1, using 1(vi) (240 mg, 0.373mmol) and Fmoc-(D)-lys(BOC)-OH (187 mg, 0.4 mmol) to yield the desiredproduct 1(vii) as an off white solid (336 mg, 82%). R_(f)=0.28 (5%MeOH/DCM).

¹H NMR (300 MHz, CDCl₃) δ 0.83, m, 6H, 1.17, m, 2H, 1.18, s, 6H, 1.40,s, 9H, 1.40, m, 2H, 1.60, m, 11H, 2.02, s, 3H, 2.51, m, 2H, 2.52, s, 3H,2.55, s, 3H, 3.02, m, 2H, 3.18, m, 2H, 3.91, m, 1H, 4.18, m, 3H, 4.52,m, 1H, 5.00, m, 2H, 6.48, br s, NH; 7.25, m, 9H, 7.43, d, J=7.6 Hz, NH;7.52, m, 2H, 7.69, d, J=7.6 Hz, 2H. MS (ES +ve) m/z 1116 (80%) [M+Na]⁺;1094 (100) [M+H]⁺.

This compound was prepared via Protocol 2, using 1(vii) (330 mg, 0.302mmol) to yield the desired product 1(viii) as an off white solid (239mg, 91%). R_(f)=baseline (5% MeOH/DCM).

¹H NMR (300 MHz, CDCl₃) δ 0.82, d, J=5.8 Hz, 3H, 0.84, d, J=5.8 Hz, 3H,1.23, m, 2H, 1.27, s, 6H, 1.38, s, 9H, 1.40, m, 2H, 1.60, m, 11H, 2.07,s, 3H, 2.52, s, 3H, 2.54, s, 3H, 2.58, m, 2H, 3.01, m, 2H, 3.19, m, 2H,3.29, m, 1H, 4.52, m, 2H, 4.92, m, NH; 5.03, ABq, J=12.3 Hz, 1H, 5.09,ABq, J=12.3 Hz, 1H, 6.39, br s, NH; 7.28, m, 5H, 7.58, d, J=7.9 Hz, NH;7.95, d, J=7.3 Hz, NH. MS (ES +ve) m/z 872 (100%) [M+H]⁺.

This compound was prepared via Protocol 1, using 1(ii) (50 mg, 0.121mmol) and 1(viii) (110 mg, 0.126 mmol) to yield the product 1(ix) as awhite solid (114 mg, 74%). R_(f)=0.16 (5% MeOH/DCM).

¹H NMR (300 MHz, CDCl₃) δ 0.46, d, J=6.2 Hz, 3H, 0.52, d, J=6.2 Hz, 3H,0.89, m, 9H, 1.20, m, 5H, 1.28, s, 6H, 1.39, m, 2H, 1.41, s, 9H, 1.70,m, 7H, 2.09, s, 3H, 2.55, s, 3H, 2.57, s, 3H, 2.61, m, 2H, 2.89, m, 2H,3.10, m, 2H, 3.86, m, 1H, 4.04, m, 2H, 4.48, m, 4H, 4.82, m, NH; 5.07,ABq, J=12.6 Hz, 1H, 5.16, ABq, J=12.6 Hz, 1H, 6.18, d, J=7.0 Hz, NH;6.29, br s, NH; 6.48, br s, NH; 7.20, m, 4H, 7.31, m, 7H, 7.45, d, J=9.1Hz, 2H, 7.85, m, 2H, 7.95, m, 2H, 8.06, d, J=8.8 Hz, NH. MS (ES +ve) m/z1291 (70%) [M+Na]⁺; 1268 (100) [M+H]⁺.

This compound was prepared via Protocol 3, using 1(ix) (104 mg, 0.082mmol) to yield the desired compound 1 as a white solid (78 mg, 98%).

¹H NMR (300 MHz, CD₃OD) δ 0.38, d, J=6.2 Hz, 3H, 0.43, d, J=6.2 Hz, 3H,0.80, m, 9H, 1.07, m, 3H, 1.52, m, 10H; 2.69, m, 2H, 3.05, m, 2H, 3.82,m, H, 4.01, m, 2H, 4.35, m, 4H, 5.03, m, 2H, 6.94, m, 2H, 7.06, m, 2H,7.21, m, 7H, 7.34, d, J=9.1 Hz, 1H, 7.42, d, J=9.1 Hz, 1H, 7.85, m, 4H.MS (ES +ve) m/z 902 (10%) [M+H]⁺; 452 (100) [M+H]²⁺.

Synthesis of Compound 2

To BOC-(L)-val-OH (100 mg, 0.48 mmol) and potassium carbonate (160 mg,1.16 mmol) in acetone (10 ml) was added benzyl bromide (0.1 ml, 0.84mmol). The resulting solution was heated at reflux overnight beforebeing cooled, filtered and evaporated to dryness. The resultant residuewas then subjected to flash column chromatography over silica, usinginitially 1:1 hexane/DCM to remove benzyl bromide, then DCM to yield theproduct 2(i) as a colourless oil (110 mg, 75%). R_(f)=0.38 (DCM)staining with Mo dip.

¹H NMR (300 MHz, CDCl₃) δ 0.84, d, J=7.0 Hz, 3H, 0.93, d, J=7.0 Hz, 3H,1.43, s, 9H, 2.14, m, 1H, 4.27, dd, J₁=9.1 Hz, J₂=4.7 Hz, 1H, 5.05,obscured d, NH; 5.07, ABq, J=12.3 Hz, 1H, 5.20, ABq, J=12.3 Hz, 1H,7.34, m, 5H. MS (ES +ve) m/z 308 (60%) [M+H]⁺; 208 (100) [M+H-Boc]⁺.

This compound was prepared via Protocol 3 using 2(i) (105 mg, 0.34 mmol)to give the product 2(ii) as an off white solid (65 mg, 92%).

¹H NMR (300 MHz, CDCl₃) δ 1.06, m, 6H, 2.44, m, 1H, 4.09, m, 1H, 5.13,ABq, J=12.0 Hz, 1H, 5.26, ABq, J=12.0 Hz, 1H, 7.32, m, 5H, 8.51, br s,NH₃ ⁺.

This compound was prepared via Protocol 1 using 2(ii) (136 mg, 0.800mmol) and Fmoc-(D)-arg(Pmc)-OH (530 mg, 0.800 mmol) to yield the desiredproduct 2(iii) as an off white solid (659 mg, 97%). R_(f)=0.40 (5%MeOH/DCM).

¹H NMR (300 MHz, CDCl₃) δ 0.79, d, J=7.0 Hz, 3H, 0.83, d, J=7.0 Hz, 3H,1.23, s, 6H, 1.60, m, 2H, 1.68, m, 3H, 1.87, m, 1H, 2.04, s, 3H, 2.11,m, 1H, 2.52, m, 2H, 2.53, s, 3H, 2.56, s, 3H, 3.20, m, 2H, 4.05, m, 1H,4.25, m, 3H, 4.45, dd, J=8.5 Hz, J₂=5.6 Hz, 1H, 5.00, ABq, J=12.3 Hz,1H, 5.10, ABq, J=12.3 Hz, 1H, 6.27, m, NH; 7.21, m, 2H, 7.26, m, 5H,7.31, m, 2H, 7.50, d, J=7.3 Hz, 2H, 7.69, d, J=7.6 Hz, 2H. MS (ES +ve)m/z 852 (100%) [M+H]⁺.

This compound was prepared via Protocol 2, using 2(iii) (604 mg, 0.709mmol) to yield the desired product 2(iv) as a colourless oil (361 mg,81%). R_(f)=baseline (5% MeOH/DCM).

¹H NMR (300 MHz, CDCl₃) δ 0.85, d, J=7.0 Hz, 3H, 0.88, d, J=7.0 Hz, 3H,1.28, s, 6H, 1.53, m, 3H, 1.77, m, 3H/NH₂; 2.08, s, 3H, 2.17, m, 1H,2.53, s, 3H, 2.55, s, 3H, 2.59, m, 2H, 3.13, m, 2H, 3.38, m, 1H, 4.40,dd, J=8.5 Hz, J₂=5.3 Hz, 1H, 5.15, ABq, J=12.3 Hz, 1H, 5.15, ABq, J=12.3Hz, 1H, 6.38, br s, NH; 7.30, m, 5H, 7.87, d, J=8.5 Hz, NH. MS (ES +ve)m/z 630 (100%) [M+H]⁺.

This compound was prepared via Protocol 1, using 2(iv) (350 mg, 0.556mmol) and Fmoc-(D)-lys(BOC)-OH (260 mg, 0.555 mmol) to yield the desiredproduct 2(v) as an off white solid (592 mg, 99%). R_(f)=0.25 (5%MeOH/DCM).

¹H NMR (300 MHz, CDCl₃) δ 0.87, m, 6H, 1.21, s, 3H, 1.22, s, 3H, 1.41,m, 13H, 1.67, m, 4H, 1.75, m, 3H, 1.88, m, 1H, 2.05, s, 3H, 2.18, m, 1H,2.52, m, 2H, 2.54, s, 3H, 2.57, s, 3H, 3.03, m, 2H, 3.19, m, 2H, 4.01,m, 1H, 4.28, m, 3H, 4.52, m, 1H, 4.61, m, 1H, 4.98, ABq, J=12.3 Hz, 1H,5.04, m, NH; 5.12, ABq, J=12.3 Hz, 1H, 6.48, br m, NH; 7.27, m, 7H,7.33, m, 2H, 7.45, d, J=8.2 Hz, NH; 7.55, m, 2H, 7.70, d, J=7.0 Hz, 2H,7.89, m, NH. MS (ES +ve) m/z 1080 (20%) [M+H]⁺; 559.8 (100) [M+H+K]²⁺.

This compound was prepared via Protocol 2, using 2(v) (350 mg, 0.324mmol) to yield the desired product 2(vi) as an off white solid (204 mg,79%). R_(f)=baseline (5% MeOH/DCM).

¹H NMR (300 MHz, CDCl₃) δ 0.82, δ, J=6.7 Hz, 3H, 0.86, d, J=6.7 Hz, 3H,1.27, s, 6H, 1.30, m, 4H, 1.38, s, 9H, 1.52, m, 2H, 1.69, m, 2H, 1.76,dist t, 2H, 1.85, m, 2H, 2.07, s, 3H, 2.12, m, 1H, 2.52, s, 3H, 2.54, s,3H, 2.58, m, 2H, 3.01, m, 2H, 3.18, m, 2H, 3.30, m, 1H, 4.46, m, 1H,4.61, m, NH; 5.02, ABq, J=12.3 Hz, 1H, 5.12, ABq, J=12.3 Hz, 1H, 6.40,br s, NH; 7.28, m, 5H, 7.52, d, J=8.5 Hz, NH; 7.99, d, J=7.0 Hz, NH. MS(ES +ve) m/z 858 (100%) [M+H]⁺.

This compound was prepared via Protocol 1, using 1(ii) (92 mg, 0.222mmol) and 2(vi) (190 mg, 0.222 mmol) to yield the product 2(vii) as awhite solid (180 mg, 65%). R_(f)=0.11 (5% MeOH/DCM).

¹H NMR (300 MHz, CDCl₃) δ 0.48, d, J=6.4 Hz, 3H, 0.53, d, J=6.4 Hz, 3H,0.82, m, 2H, 0.87, t, J=7.0 Hz, 6H, 1.18, m, 6H, 1.28, s, 6H, 1.41, s,9H, 1.60, m, 1H, 1.76, dist t, 2H, 1.85, m, 1H, 2.08, s, 3H, 2.20, m,1H, 2.54, s, 3H, 2.56, s, 3H, 2.58, m, 2H, 2.89, m, 2H, 3.14, m, 2H,3.87, m, 1H, 4.06, m, 2H, 4.45, m, 4H, 4.82, m, NH; 5.08, ABq, J=12.3Hz, H, 5.19, ABq, J=12.3 Hz, 1H, 6.22, m, NH; 7.13, m, 2H, 7.25, m, 2H,7.35, m, 8H, 7.46, d, J=9.1 Hz, 1H, 7.83, d, J=7.6 Hz, 1H, 7.85, d,J=7.9 Hz, 1H, 7.93, d, J=8.8 Hz, 1H, 7.94, d, J=9.1 Hz, 1H. MS (ES +ve)m/z 1255 (100%) [M+H]⁺.

This compound was prepared via Protocol 3, using 2(vii) (100 mg, 0.080mmol) to yield the product 2 as a white solid (49 mg, 64%).

¹H NMR (300 MHz, CD₃OD) δ 0.51, d, J=6.5 Hz, 3H, 0.56, d, J=6.5 Hz, 3H,0.92, d, J=6.7 Hz, 6H, 0.94, m, 1H, 1.18, m, 3H, 1.61, m, 6H, 2.18, m,1H, 2.79, m, 2H, 3.16, m, 2H, 3.94, m, 1H, 4.10, m, 2H, 4.48, m, 4H,5.13, ABq, J=12.3 Hz, 1H, 5.20, ABq, J=12.3 Hz, 1H, 7.06, m, 2H, 7.20,dist t, 2H, 7.35, m, 7H, 7.46, d, J=8.8 Hz, 1H, 7.55, d, J=9.1 Hz, 1H,7.89, d, J=7.9 Hz, 1H, 7.91, d, J=8.2 Hz, 1H, 8.00, d, J=9.1 Hz, 2H. MS(ES +ve) m/z 888 (10%) [M+H]⁺; 445 (100) [M+2H]²⁺.

Synthesis of Compound 3

To BOC-(L)-Ile-OH (200 mg, 0.86 mmol) and potassium carbonate (300 mg,2.16 mmol) in acetone (20 ml) was added benzyl bromide (0.2 ml, 1.72mmol). The resulting solution was heated at reflux overnight beforebeing cooled, filtered and evaporated to dryness. The resultant residuewas subjected to flash column chromatography over silica, eluting firstwith 1:1 hexane/DCM to remove benzyl bromide, then with DCM. The product3(i) was isolated as a colourless oil (253 mg, 91%). R_(f)=0.28 (DCM)using Mo stain.

¹H NMR (300 MHz, CDCl₃) δ 0.88, m, 6H, 1.12, m, 1H, 1.38, m, 1H, 1.43,s, 9H, 1.86, m, 1H, 4.31, m, 1H, 5.05, m, NH; 5.10, ABq, J=12.3 Hz, 1H,5.20, ABq, J=12.3 Hz, 1H, 7.33, m, 5H.

This compound was prepared via Protocol 3, using 3(i) (115 mg, 0.358mmol) to yield the desired product 3(ii) as an off white solidhydrochloride salt (80 mg, 87%).

¹H NMR (300 MHz, CDCl₃) δ 0.90, t, J=7.1 Hz, 3H, 1.03, d, J=6.8 Hz, 3H,1.43, m, 2H, 2.16, m, 1H, 4.14, m, 1H, 5.13, ABq, J=12.0 Hz, 1H, 5.26,ABq, J=12.0 Hz, 1H, 7.33, m, 5H, 8.62, br s, NH₃ ⁺.

This compound was prepared via Protocol 1 using 3(ii) (173 mg, 0.778mmol) and Fmoc-(D)-arg(Pmc)-OH (520 mg, 0.785 mmol) to yield the desiredproduct 3(iii) as an off white solid (452 mg, 79%). R_(f)=0.40 (5%MeOH/DCM).

¹H NMR (300 MHz, CDCl₃) δ 0.75, m, 6H, 1.11, m, 1H, 1.23, s, 6H, 1.30,m, 1H, 1.60, m, 2H, 1.70, dist t, 2H, 1.86, m, 2H, 1.99, m, 1H, 2.05, s,3H, 2.50, m, 2H, 2.53, s, 3H, 2.56, s, 3H, 3.20, m, 2H, 4.06, dist t,1H, 4.25, m, 3H, 4.50, dd, J=8.3 Hz, J₂=5.3 Hz, 1H, 5.01, ABq, J=12.0Hz, 1H, 5.12, ABq, J=12.3 Hz, 1H, 6.13, br s, NH; 6.27, s, NH; 7.19,dist t, 2H, 7.26, m, 5H, 7.33, dist t, 2H, 7.51, d, J=7.5 Hz, 2H, 7.6,dist t, NH; 7.70, d, J=7.8 Hz, 2H. MS (ES +ve) m/z 866 (100%) [M+H]⁺.

This compound was prepared via Protocol 2, using 3(iii) (540 mg, 0.623mmol) to yield the desired product 3(iv) as a white solid (338 mg, 84%).R_(f)=baseline (5% MeOH/DCM).

¹H NMR (300 MHz, CDCl₃) δ 0.85, m, 6H, 1.13, m, 1H, 1.28, s, 6H, 1.34,m, 1H, 1.54, m, 3H, 1.66, m, 1H, 1.77, dist t, 2H, 1.90, m, 1H, 2.08, s,3H, 2.54, s, 3H, 2.56, s, 3H, 2.60, dist t, 2H, 3.13, m, 2H, 3.37, m,1H, 4.45, dd, J=8.5 Hz, J₂=5.3 Hz, 1H, 5.04, ABq, J=12.3 Hz, 1H, 5.16,ABq, J=12.3 Hz, 1H, 6.31, br s, NH; 6.38, br s, NH; 7.30, m, 5H, 7.87,d, J=8.5 Hz, NH. MS (ES +ve) m/z 644 (100%) [M+H]⁺.

This compound was prepared via Protocol 1, using 3(iv) (300 mg, 0.466mmol) and Fmoc-(D)-lys(BOC)-OH (218 mg, 0.465 mmol) to yield the desiredproduct 3(v) as an off white solid (388 mg, 76%). R_(f)=0.25 (5%MeOH/DCM).

¹H NMR (300 MHz, CDCl₃) δ 0.83, m, 6H, 1.16, m, 1H, 1.21, s, 3H, 1.22,s, 3H, 1.38, m, 4H, 1.40, s, 9H, 1.67, m, 8H, 1.92, m, 2H, 2.04, s, 3H,2.52, m, 2H, 2.53, s, 3H, 2.56, s, 3H, 3.03, m, 2H, 3.18, m, 2H, 4.01,dist t, 1H, 4.26, m, 3H, 4.54, m, 2H, 4.95, m, NH; 4.98, ABq, J=12.3 Hz,1H, 5.13, ABq, J=12.3 Hz, 1H, 6.20, br s, NH; 6.41, br s, NH; 7.27, m,9H, 7.54, m, 2H, 7.70, d, J=7.3 Hz, 2H. MS (ES +ve) m/z 1116 (80%)[M+Na]⁺; 1094 (100) [M+H]⁺.

This compound was prepared via Protocol 2, using 3(v) (388 mg, 0.355mmol) to yield the desired product 3(vi) as an off white solid (268 mg,87%). R_(f)=baseline (5% MeOH/DCM).

¹H NMR (300 MHz, CDCl₃) δ 0.82, m, 6H, 1.15, m, 1H, 1.26, s, 6H, 1.31,m, 2H, 1.37, m, 2H, 1.38, s, 9H, 1.51, m, 2H, 1.71, m, 6H, 1.86, m, 2H,2.07, s, 3H, 2.52, s, 3H, 2.54, s, 3H, 2.59, m, 2H, 3.02, m, 2H, 3.18,m, 2H, 3.30, m, 1H, 4.51, m, 1H, 4.58, m, 1H, 4.93, m, NH; 5.01, ABq,J=12.3 Hz, 1H, 5.13, ABq, J=12.3 Hz, 1H, 6.39, br s, NH; 7.28, m, 5H,7.49, d, J=8.5 Hz, NH; 7.98, d, J=7.9 Hz, NH. MS (ES +ve) m/z 872 (100%)[M+H]⁺.

This compound was prepared via Protocol 1, using 1(ii) (119 mg, 0.287mmol) and 3(vi) (250 mg, 0.287 mmol) to yield the product 3(vii) as awhite solid (171 mg, 47%). R_(f)=0.07 (5% MeOH/DCM).

¹H NMR (300 MHz, CDCl₃) δ 0.48, d, J=6.4 Hz, 3H, 0.53, d, J=6.4 Hz, 3H,0.87, m, 7H, 0.96, m, 1H, 1.20, m, 11H, 1.27, s, 6H, 1.41, s, 9H, 1.59,m, 1H, 1.75, m, 2H, 1.84, m, 1H, 1.92, m, 1H, 2.08, s, 3H, 2.54, s, 3H,2.56, s, 3H, 2.57, m, 2H, 2.88, m, 2H, 3.11, m, 2H, 3.87, m, 1H, 4.09,m, 2H, 4.49, m, 4H, 5.07, ABq, J=12.3 Hz, 1H, 5.19, ABq, J=12.3 Hz, 1H,6.24, br s, NH; 7.31, m, 12H, 7.44, d, J=9.1 Hz, 1H, 7.84, m, 2H, 7.92,m, 2H. MS (ES +ve) m/z 1269 (100%) [M+H]⁺.

This compound was prepared via Protocol 3, using 3(vii) (170 mg, 0.134mmol) to yield the product 3 as a white solid (127 mg, 97%).

¹H NMR (300 MHz, CD₃OD) δ 0.48, d, J=6.2 Hz, 3H, 0.53, d, J=6.2 Hz, 3H,0.87, m, 7H, 0.96, m, 1H, 1.17, m, 5H, 1.57, m, 8H, 1.79, m, 1H, 1.91,m, 1H, 2.81, m, 2H, 3.16, m, 2H, 3.92, m, 1H, 4.10, m, 1H, 4.19, m, 1H,4.43, m, 4H, 5.10, ABq, J=12.3 Hz, 1H, 5.19, ABq, J=12.3 Hz, 1H, 7.05,m, 2H, 7.16, m, 2H, 7.33, m, 7H, 7.43, d, J=9.1 Hz, 1H, 7.53, d, J=9.1Hz, 1H, 7.85, m, 2H, 7.99, m, 2H. MS (ES +ve) m/z 902 (10%) [M+H]⁺;452.0 (100) [M+2H]²⁺.

Synthesis of Compound 4

To BOC(L)-Leu-OH (250 mg, 1.08 mmol) and potassium carbonate (747 mg,5.40 mmol) in acetone (50 ml) was added 4-chlorobenzyl bromide (333 mg,1.62 mmol). The resulting solution was heated at reflux overnight beforebeing cooled, filtered and evaporated to dryness. The resultant residuewas subjected to flash column chromatography over silica, eluting with1:4 hexane/DCM to first remove 4-chlorobenzyl bromide, then with DCM toyield the product 4(i) as a colourless oil (366 mg, 95%). R_(f)=0.55(DCM) using Mo dip.

¹H NMR (300 MHz, CDCl₃) δ 0.89, d, J=6.4 Hz, 3H, 0.90, d, J=6.4 Hz, 3H,1.41, s, 9H, 1.48, m, 2H, 1.64, m, 1H, 4.31, m, 1H, 4.95, d, J=8.2 Hz,NH; 5.06, ABq, J=12.3 Hz, 1H, 5.13, ABq, J=12.3 Hz, 1H, 7.25, ABq, J=8.4Hz, 2H, 7.30, ABq, J=8.2 Hz, 2H. MS (ES +ve) m/z 356 (100%) [M+H]⁺.

This compound was prepared via Protocol 4, using 4(i) (366 mg, 1.03mmol) to yield the desired product 4(ii) as a colourless oil (235 mg,89%).

¹H NMR (300 MHz, CDCl₃) δ 0.88, d, J=6.4 Hz, 3H, 0.91, d, J=6.4 Hz, 3H,1.43, m, 1H, 1.55, m, 1H, 1.56, m, NH₂; 1.74, m, 1H, 3.48, m, 1H, 5.09,s, 2H, 7.27, ABq, J=8.5 Hz, 2H, 7.32, ABq, J=8.5 Hz, 2H. MS (ES +ve) m/z256 (100%) [M+H]⁺.

This compound was prepared via Protocol 1 using 4(ii) (235 mg, 0.919mmol) and Fmoc-(D)-arg(Pmc)-OH (609 mg, 0.919 mmol) to yield the desiredproduct 4(iii) as an off white solid (806 mg, 97%).

¹H NMR (500 MHz, CDCl₃) δ 0.79, dist d, 6H, 1.28, s, 6H, 1.65, m, 8H,1.89, m, 1H, 2.03, s, 3H, 2.49, m, 2H, 2.53, s, 3H, 2.56, s, 3H, 3.23,m, 2H, 4.03, m, 1H, 4.28, m, 3H, 4.51, m, 1H, 4.96, ABq, J=12.2 Hz, 1H,5.02, ABq, J=12.2 Hz, 1H, 6.42, br s, NH; 7.19, m, 6H, 7.31, dist t, 2H,7.49, dist d, 2H, 7.54, d, J=7.8 Hz, NH; 7.68, ABq, J=7.8 Hz, 2H. MS (ES+ve) m/z 900 (100%) [M+H]⁺.

This compound was prepared via Protocol 2, using 4(iii) (798 mg, 0.887mmol) to yield the desired product 4(iv) as an off white solid (532 mg,88%).

¹H NMR (500 MHz, CDCl₃) δ 0.76, d, J=6.1 Hz, 3H, 0.88, d, J=6.1 Hz, 3H,1.28, s, 6H, 1.57, m, 5H/NH₂; 1.77, m, 3H, 2.02, m, 1H, 2.08, s, 3H,2.53, s, 3H, 2.55, s, 3H, 2.59, m, 2H, 3.15, m, 2H, 3.41, m, 1H, 4.49,m, 1H, 5.01, ABq, J=12.2 Hz, 1H, 5.07, ABq, J=12.2 Hz, 1H, 6.45, br s,NH; 7.22, ABq, J=8.5 Hz, 2H, 7.26, ABq, J=8.5 Hz, 2H, 7.83, d, J=7.9 Hz,NH. MS (ES +ve) m/z 678 (100%) [M+H]⁺.

This compound was prepared via Protocol 1, using 4(iv) (519 mg, 0.765mmol) and Fmoc-(D)-lys(BOC)-OH (359 mg, 0.766 mmol) to yield the desiredproduct 4(v) as an off white solid (785 mg, 91%).

¹H NMR (500 MHz, CDCl₃) δ 0.82, d, J=5.5 Hz, 3H, 0.84, d, J=5.9 Hz, 3H,1.19, br s, 6H, 1.39, s, 9H, 1.63, m, 14H, 2.02, s, 3H, 2.05, m, 1H,2.51, m, 2H, 2.52, s, 3H, 2.55, s, 3H, 3.02, m, 2H, 3.19, m, 2H, 3.94,m, 1H, 4.14, m, 3H, 4.53, m, 2H, 4.95, m, 2H/NH; 6.47, br m, NH; 7.19,m, 4H, 7.32, m, 2H, 7.54, m, 4H, 7.69, m, 2H. MS (ES +ve) m/z 1128(100%) [M+H]⁺.

This compound was prepared via Protocol 2, using 4(v) (330 mg, 0.292mmol) to yield the desired product 4(vi) as an off white solid (236 mg,89%).

¹H NMR (500 MHz, CDCl₃) δ 0.85, d, J=5.9 Hz, 3H, 0.87, d, J=5.9 Hz, 3H,1.29, s, 6H, 1.48, s, 9H, 1.57, m, 14H/NH₂; 2.09, s, 3H, 2.13, m, 1H,2.54, s, 3H, 2.56, s, 3H, 2.60, m, 2H, 3.04, m, 2H, 3.22, m, 2H, 3.35,m, 1H, 4.52, m, 1H, 4.59, m, 1H, 4.98, m, NH; 5.02, ABq, J=12.2 Hz, 1H,5.07, ABq, J=12.2 Hz, 1H, 6.45, br s, NH; 7.23, ABq, J=8.5 Hz, 2H, 7.28,ABq, J=8.5 Hz, 2H, 7.71, m, NH; 8.00, m, NH. MS (ES +ve) m/z 906 (100%)[M+H]+.

This compound was prepared via Protocol 1, using 1(ii) (105 mg, 0.254mmol) and 4(vi) (230 mg, 0.254 mmol) to yield the product 4(vii) as awhite solid (144 mg, 44%).

¹H NMR (500 MHz, CDCl₃) δ 0.46, d, J=5.3 Hz, 3H, 0.52, d, J=5.3 Hz, 3H,0.79, m, 2H, 0.87, d, J=5.9 Hz, 3H, 0.89, d, J=5.9 Hz, 3H, 0.94, m, 1H,1.19, m, 6H, 1.28, s, 6H, 1.29, m, 2H, 1.41, s, 9H, 1.64, m, 4H, 1.76,m, 2H, 1.84, m, 1H, 2.09, s, 3H, 2.54, s, 3H, 2.56, s, 3H, 2.58, m, 2H,2.90, m, 2H, 3.15, m, 2H, 3.87, m, 1H, 4.04, m, 2H, 4.41, m, 2H, 4.45,m, 3H, 4.82, m, NH; 5.04, ABq, J=12.2 Hz, 1H, 5.11, ABq, J=12.2 Hz, 1H,6.19, d, J=6.8 Hz, NH; 6.29, br s, NH; 7.26, m, 11H, 7.44, d, J=9.1 Hz,1H, 7.83, d, J=8.3 Hz, 1H, 7.85, d, J=8.3 Hz, 1H, 7.93, d, J=9.0 Hz, 1H,7.94, d, J=8.9 Hz, 1H. MS (ES +ve) m/z 1302 (60%) [M+H]⁺; 602 (100)[M+2H-BOC]⁺.

This compound was prepared via Protocol 3, using 4(vii) (140 mg, 0.107mmol) to yield the desired product 4 as a white solid (101 mg, 93%).

¹H NMR (500 MHz, CD₃OD) δ 0.40, d, J=6.3 Hz, 3H, 0.45, d, J=6.3 Hz, 3H,0.78, d, J=4.8 Hz, 3H, 0.83, d, J=4.8 Hz, 3H, 0.84, m, 2H, 1.05, m, 2H,1.13, m, 2H, 1.53, m, 9H, 1.72, m, 1H, 2.70, m, 2H, 3.06, m, 2H, 3.84,m, 1H, 4.03, m, 2H, 4.36, m, 4H, 5.02, s, 2H, 7.06, dist t, 2H, 7.18, m,2H, 7.33, m, 6H, 7.45, d, J=9.3 Hz, 1H, 7.54, d, J=8.8 Hz, 1H, 7.88, d,J=7.8 Hz, 1H, 7.91, d, J=8.3 Hz, 1H, 8.00, dist t, 2H. MS (ES +ve) m/z936 (15%) [M+H]⁺; 469 (100) [M+2H]²⁺.

Synthesis of Compound 5

To BOC(L)-Leu-OH (250 mg, 1.08 mmol) and potassium carbonate (747 mg,5.40 mmol) in acetone (50 ml) was added 4-nitrobenzyl bromide (350 mg,1.62 mmol). The resulting solution was heated at reflux overnight beforebeing cooled, filtered and evaporated to dryness. The resultant residuewas subjected to flash column chromatography over silica, eluting with1:4 hexane/DCM to first remove 4-nitrobenzyl bromide, then with DCM toyield the product 5(i) as a colourless oil.

¹H NMR (500 MHz, CDCl₃) δ 0.95, d, J=6.8 Hz, 6H, 1.44, s, 9H, 1.53, m,1H, 1.63, m, 1H, 1.71, m, 1H, 4.38, m, 1H, 4.99, d, J=8.3 Hz, NH; 5.27,s, 2H, 7.53, ABq, J=8.3 Hz, 2H, 8.22, ABq, J=8.3 Hz, 2H. MS (EI) m/z 265(100%) [M-BOC]⁺.

To 5(i) (215 mg, 0.59 mmol) in DCM (2 ml) was added TFA (2 ml) and theresulting solution stirred at room temperature for 3 hrs. The solutionwas then diluted with DCM (5 ml) and washed with sat. sodium bicarbonatesolution until the washings were basic. The organic layer was then dried(MgSO₄), filtered and evaporated to dryness to yield the desired product5(ii) as a white solid (131 mg, 84%).

¹H NMR (500 MHz, CDCl₃) δ 0.93, d, J=8.8 Hz, 3H, 0.95, d, J=8.8 Hz, 3H,1.50, m, 1H, 1.62, m, 1H, 1.54, m, 1H, 1.79, m, 1H, 2.37, br s, NH₂;3.61, m, 1H, 5.26, s, 2H, 7.54, ABq, J=8.8 Hz, 2H, 8.22, ABq, J=8.8 Hz,2H. MS (ES +ve) m/z 267 (100%) [M+H]⁺.

This compound was prepared via Protocol 1 using 5(ii) (130 mg, 0.488mmol) and Fmoc-(D)-arg(Pmc)-OH (323 mg, 0.488 mmol) to yield the desiredproduct 5(iii) as a white solid (414 mg, 93%).

¹H NMR (500 MHz, CDCl₃) δ 0.83, br s, 6H, 1.21, s, 6H, 1.61, m, 4H,1.66, m, 3H, 1.75, m, 2H, 2.03, s, 3H, 2.49, m, 2H, 2.53, s, 3H, 2.57,s, 3H, 3.23, m, 2H, 4.01, m, 1H, 4.23, m, 2H, 4.36, m, 1H, 4.56, m, 1H,5.09, s, 2H, 6.45, br s, NH; 7.17, m, 2H, 7.29, m, 5H (inc NH); 7.48,ABq, J=8.8 Hz, 2H, 7.66, m, 2H, 7.70, m, NH; 8.04, ABq, J=8.8 Hz, 2H. MS(ES +ve) m/z 911 (100%) [M+H]⁺.

This compound was prepared via Protocol 2, using 5(iii) (400 mg, 0.439mmol) to yield the desired product 5(iv) as an off white solid (210 mg,69%).

¹H NMR (500 MHz, CDCl₃) δ 0.90, dist d, 6H, 1.28, s, 6H, 1.57, m, 4H,1.65, m, 2H, 1.78, m, 3H, 2.07, s, 3H, 2.52, s, 3H, 2.54, s, 3H, 2.59,m, 2H, 3.17, m, 2H, 3.49, m, 1H, 4.53, m, 1H, 5.20, s, 2H, 6.45, br s,NH; 7.47, ABq, J=8.3 Hz, 2H, 7.90, d, J=5.4 Hz, NH. 8.22, ABq, J=8.3 Hz,2H. ¹³C NMR (125 MHz, CDCl₃) δ 12.0, 17.3, 18.4, 21.2, 21.5, 22.6, 22.9,24.8, 25.2, 26.6, 31.6, 32.6, 40.2, 50.7, 54.0, 65.2, 73.5, 117.9,123.6, 123.9, 128.2, 133.1, 134.6, 135.2, 142.7, 147.5, 153.5, 156.3,172.4, 175.3. MS (ES +ve) m/z 689 (100%) [M+H]⁺.

The Fmoc-protected precursor to this compound was prepared via Protocol4, using 5(iv) (200 mg, 0.290 mmol) and Fmoc-(D)-lys(BOC)-OH (136 mg,0.290 mmol) to yield the Fmoc-protected derivative 5(v) as an off whitesolid. The desired deprotected compound was prepared via Protocol 2, toyield the product 5(vi) as an off white solid (201 mg, 76%).

¹H NMR (500 MHz, CDCl₃) δ 0.87, d, J=5.8 Hz, 3H, 0.90, d, J=5.8 Hz, 3H,1.29, s, 6H, 1.40, s, 9H, 1.60, m, 15H, 2.08, s, 3H, 2.54, s, 3H, 2.56,s, 3H, 2.60, m, 2H, 3.04, m, 2H, 3.23, m, 2H, 3.51, m, 1H, 4.58, m, 2H,4.93, m, NH; 5.19, s, 2H, 6.44, br s, NH; 7.48, ABq, J=8.8 Hz, 2H, 7.77,m, NH; 8.01, m, NH; 8.16, ABq, J=8.8 Hz, 2H. MS (ES +ve) m/z 917 (10%)[M+H]⁺; 431.5 (100) [M+H-C₄H₈]⁺.

This compound was prepared via Protocol 1, using 1(ii) (91 mg, 0.022mmol) and 5(vi) (190 mg, 0.021 mmol) to yield the product 5(vii) as awhite solid (194 mg, 71%).

¹H NMR (500 MHz, CDCl₃) δ 0.46, d, J=6.3 Hz, 3H, 0.51, d, J=6.3 Hz, 3H,0.89, d, J=5.8 Hz, 3H, 0.90, m, 2H, 0.92, d, J=5.8 Hz, 3H, 1.25, m, 4H,1.26, s, 6H, 1.40, s, 9H, 1.56, m, 10H; 1.83, m, 1H, 2.07, s, 3H, 2.53,s, 3H, 2.56, s, 3H, 2.58, m, 2H, 2.90, m, 2H, 3.15, m, 2H, 3.93, m, 3H,4.51, m, 4H, 5.22, s, 2H, 6.20, d, J=7.0 Hz, NH; 6.29, br s, NH; 7.04,d, J=7.3 Hz, H, 7.06, d, J=8.3 Hz, 1H, 7.17, m, 2H, 7.31, t, J=7.3 Hz,2H, 7.45, d, J=9.3 Hz, 1H, 7.53, d, J=9.3 Hz, 1H, 7.58, ABq, J=8.8 Hz,2H, 7.87, d, J=8.3 Hz, 1H, 7.89, d, J=8.3 Hz, H, 7.99, d, J=8.8 Hz, 1H,8.00, d, J=9.3 Hz, 1H, 8.19, ABq, J=8.8 Hz, 2H. MS (ES +ve) m/z 1313(100%) [M+H]⁺.

This compound was prepared via Protocol 3, using 5(vii) (194 mg, 0.015mmol) to yield an impure product. Protocol 3 was repeated on 130 mg ofthis product to yield the desired product 5 as an off white solid (110mg, 84%).

¹H NMR (500 MHz, CD₃OD) δ 0.38, d, J=6.4 Hz, 3H, 0.44, d, J=6.4 Hz, 3H,0.80, d, J=5.5 Hz, 3H, 0.85, d, J=5.5 Hz, 3H, 0.90, m, 2H, 1.10, m, 4H,1.56, m, 9H, 1.74, m, 1H, 2.70, m, 2H, 3.06, m, 2H, 3.83, m, 1H, 4.02,m, 2H, 4.27, m, 1H, 4.36, ABq, J=14.5 Hz, 1H, 4.40, m, 1H, 4.46, ABq,J=14.5 Hz, 1H, 5.26, s, 2H, 7.04, d, J=7.3 Hz, 1H, 7.06, d, J=8.3 Hz,1H, 7.17, m, 2H, 7.31, t, J=7.3 Hz, 2H, 7.45, d, J=9.3 Hz, H, 7.53, d,J=9.3 Hz, 1H, 7.58, ABq, J=8.8 Hz, 2H, 7.87, d, J=8.3 Hz, 1H, 7.89, d,J=8.3 Hz, 1H, 7.99, d, J=8.8 Hz, 1H, 8.00, d, J=9.3 Hz, 1H, 8.19, ABq,J=8.8 Hz, 2H. MS (ES +ve) m/z 947 (10%) [M+H]⁺; 474.5 (100) [M+2H]²⁺.

Synthesis of Compound 6

To BOC-(L)-leu-OH (250 mg, 1.08 mmol) and potassium carbonate (1.00 g,7.24 mmol) in acetone (25 ml) was added 2-chlorobenzyl bromide (0.16 ml,1.22 mmol). The resulting solution was heated at reflux overnight beforebeing cooled, filtered and evaporated to dryness. The resultant residuewas subjected to flash column chromatography over silica, eluting with5% ethyl acetate/hexane to first remove 2-chlorobenzyl bromide, thenwith DCM to yield the product 6(i) as a white solid (370 mg, 96%).

¹H NMR (500 MHz, CDCl₃) δ 0.92, d, J=6.3 Hz, 3H, 0.93, d, J=6.3 Hz, 3H,1.43, s, 9H, 1.54, m, 1H, 1.68, m, 2H, 4.36, m, 1H, 5.08, m, NH; 5.13,m, 2H, 7.22, m, 1H, 7.27, m, 2H, 7.34, s, 1H. MS (ES +ve), m/z 357(100%) [M+H]⁺; 257 (70) [M+H-BOC]⁺.

To 6(i) (360 mg, 1.01 mmol) in DCM (2 ml) was added TFA (2 ml) and theresulting solution stirred at room temperature for 3 hrs. The solutionwas then diluted with DCM (5 ml) and washed with sat. sodium bicarbonatesolution until the washings were basic. The organic layer was then dried(MgSO₄), filtered and evaporated to dryness to yield the desired product6(ii) as a pale yellow oil (179 mg, 69%).

¹H NMR (500 MHz, CDCl₃) δ 0.85, d, J=6.8 Hz, 3H, 0.87, d, J=6.8 Hz, 3H,1.41, m, 1H, 1.52, m, 1H, 1.71, m, 1H, 2.41, br s NH₂; 3.50, m, 1H,5.05, s, 2H, 7.18, m, 1H, 7.23, m, 2H, 7.28, s, 1H. MS (ES +ve) m/z256.0 (100%) [M+H]⁺.

This compound was prepared in two steps. The first step via Protocol 1,using 6(ii) (170 mg, 0.67 mmol) and Fmoc-(D)-arg(Pmc)-OH (398 mg, 0.60mmol) to yield the Fmoc protected precursor 6(iii) as an off white foamysolid (529 mg, MS (ES +ve) m/z 900.0 (100%) [M+H]⁺). The desired productwas then prepared via Protocol 2, using precursor 6(iii) (230 mg, 0.26mmol) to afford the product 6(iv) as a colourless oil (150 mg, 85% twosteps).

¹H NMR (500 MHz, CDCl₃) δ 0.80, d, J=6.4 Hz, 3H, 0.82, d, J=6.4 Hz, 3H,1.21, s, 6H, 1.51, m, 5H, 1.70, m, 3H, 2.01, s, 3H, 2.03, m, 1H, 2.46,s, 3H, 2.48, s, 3H, 2.52, m, 2H, 3.08, m, 2H, 3.36, m, 1H, 4.42, m, 1H,4.95, ABq, J=12.3 Hz, 1H, 5.01, ABq, J=12.3 Hz, H, 6.32, br s, NH; 7.15,m, 4H, 7.76, d, J=6.8 Hz, NH. MS (ES +ve) m/z 678.0 (100%) [M+H]⁺. HRMSfor C₃₃H₄₈ClN₅O₆S, calculated 678.3092, found 678.3094.

This compound was prepared via Protocol 1, using 1(ii) (642 mg, 1.55mmol) and (D)-lys(BOC)-OMe (400 mg, 1.54 mmol) to yield the desiredcompound 6(v) as a off white sticky solid (898 mg, 89%). R_(f)=0.53 (5%MeOH/DCM).

¹H NMR (500 MHz, CDCl₃) δ 0.54, d, J=6.4 Hz, 3H, 0.58, d, J=6.4 Hz, 3H,0.78, m, 2H, 1.00, m, 1H, 1.22, m, 6H, 1.42, s, 9H, 2.91, m, 2H, 3.59,s, 3H, 3.95, m, 1H, 4.06, m, 1H, 4.29, m, 1H, 4.45, ABq, J=14.3 Hz, 1H,4.51, ABq, J=14.3 Hz, 1H, 4.64, br s, NH; 6.15, d, J=8.5 Hz, NH; 7.17,m, 4H, 7.30, m, 3H, 7.46, d, J=8.9 Hz, 1H, 7.83, d, J=7.5 Hz, 1H, 7.84,d, J=7.8 Hz, 1H, 7.92, d, J=10.2 Hz, 1H, 7.94, d, J=10.2 Hz, 1H. MS (ES)m/z 657.1 (100%) [M+H]⁺; 557.1 (90) [M+H-BOC]⁺.

To a solution of 6(v) (898 mg, 1.37 mmol) in THF (20 ml) was added asolution of LiOH.H₂O (1260 mg, 30.1 mmol) in water (10 ml). Theresultant solution was stirred at RT for 1 hr before diethyl ether (20ml) was added and the layer separated. The aqueous layer was extractedwith sat. sodium bicarbonate solution and the aqueous extracts combinedthen acidified to pH ˜2-3 using 1M potassium bisulphate. The aqueouslayer was then extracted with DCM (3×20 ml). A TLC of the initial andfinal organic layers was completed and showed the product was in bothlayers. As a result, all of the organic fractions were combined, dried(MgSO₄) and evaporated to dryness to yield the product 6(vi) as an offwhite foamy solid (854, 97%).

¹H NMR (300 MHz, CDCl₃) δ 0.53, d, J=6.3 Hz, 3H, 0.57, d, J=6.3 Hz, 3H,0.82, m, 2H, 1.24, m, 5H, 1.40, m, 2H (obscured by BOC-CH₃); 1.44, s,9H, 2.92, m, 2H, 3.95, m, 1H, 4.05, m, 1H, 4.31, m, 1H, 4.49, ABq,J=14.6 Hz, 1H, 4.57, ABq, J=14.6 Hz, 1H, 4.60, br s, NH (obscured byABq); 6.15, m, NH; 7.19, m, 4H, 7.32, m, 3H, 7.44, d, J=9.1 Hz, 1H,7.85, d, J=8.0 Hz, 1H, 7.86, d, J=8.1 Hz, 1H, 7.94, d, J=9.0 Hz, 1H,7.96, d, J=9.1 Hz, 1H. MS (ES+ve) 643.1 (100%) [M+H]⁺; 543.1 (30)[M+H-BOC]⁺.

This compound was prepared via Protocol 1, using 6(vi) (122 mg, 0.186mmol) and 6(iv) (145 mg, 0.199 mmol) to yield 6(vii) as a white solid(198 mg, 82%).

¹H NMR (500 MHz, CDCl₃) δ 0.39, d, J=6.5 Hz, 3H, 0.44, d, J=6.5 Hz, 3H,0.70, m, 2H, 0.80, d, J=5.6 Hz, 3H, 0.82, d, J=5.6 Hz, 3H, 0.89, m, 1H,1.12, m, 6H, 1.19, s, 6H, 1.29, m, 2H, 1.33, s, 9H, 1.55, m, 4H, 1.68,m, 2H, 1.71, m, 1H, 2.00, s, 3H, 2.48, s, 3H, 2.48, s, 3H, 2.50, m, 2H,2.82, m, 2H, 3.07, m, 2H, 3.79, m, 1H, 3.96, m, 2H, 4.33, m, 2H, 4.44,m, 3H, 4.73, m, NH; 4.97, ABq, J=12.7 Hz, 1H, 5.03, ABq, J=12.7 Hz, 1H,6.12, d, J=6.9 Hz, NH; 6.22, br s, NH; 7.26, m, 11H, 7.36, d, J=9.1 Hz,1H, 7.75, d, J=10.1 Hz, 1H, 7.77, d, J=8.7 Hz, 1H, 7.84, d, J=8.7 Hz,1H, 7.86, d, J=7.6 Hz, 1H. MS (ES +ve) m/z 1301.9 (100%) [M+H]⁺; 602.6(30) [M+2H-BOC]²⁺.

This compound was prepared via Protocol 3, using 6(vii) (180 mg, 0.138mmol) to yield 6 as an off white solid (130 mg, 93%).

¹H NMR (500 MHz, CD₃OD) δ 0.50, d, J=6.3 Hz, 3H, 0.55, d, J=6.3 Hz, 3H,0.90, d, J=4.8 Hz, 3H, 0.94, d, J=4.8 Hz, 3H, 0.95, m, 2H, 1.14, m, 2H,1.23, m, 2H, 1.67, m, 10H, 2.83, m, 2H, 3.18, m, 2H, 3.96, m, 1H, 4.14,m, 2H, 4.36, m, 1H, 4.48, m, 3H, 5.12, s, 2H, 7.05, d, J=3.7 Hz, 1H,7.08, d, J=3.5 Hz, 1H, 7.17, dist t, 2H, 7.30, m, 5H, 7.38, s, 1H, 7.45,d, J=9.0 Hz, 1H, 7.54, d, J=9.0 Hz, 1H, 7.88, d, J=8.5 Hz, 1H, 7.91, d,J=8.5 Hz, 1H, 7.99, d, J=8.7 Hz, 1H, 8.02, d, J=8.5 Hz, 1H. MS (ES +ve)m/z 935.7 (5%) [M+H]⁺; 468.7 (100) [M+2H]²⁺.

Synthesis of Compound 7

To BOC-(L)-leu-OH (250 mg, 1.08 mmol) and potassium carbonate (1.00 g,7.24 mmol) in acetone (25 ml) was added 2-chlorobenzyl bromide (0.16 ml,1.23 mmol). The resulting solution was heated at reflux overnight beforebeing cooled, filtered and evaporated to dryness. The resultant residuewas subjected to flash column chromatography over silica, eluting with5% ethyl acetate/hexane to first remove 2-chlorobenzyl bromide, thenwith DCM to yield the product 7(i) as a white solid (353 mg, 92%).

¹H NMR (500 MHz, CDCl₃) δ 0.92, d, J=6.4 Hz, 3H, 0.93, d, J=6.4 Hz, 3H,1.43, s, 9H, 1.56, m, 1H, 1.68, m, 2H, 4.40, m, 1H, 5.16, d, J=8.4 Hz,NH; 5.22, ABq, J=13.1 Hz, 1H, 5.27, ABq, J=13.1 Hz, 1H, 7.25, m, 2H,7.35, m, 1H, 7.42, m, 1H. MS (ES +ve) m/z 356.1 (100%) [M+H]⁺; 256.0(70) [M+H-BOC]⁺.

To 7(i) (350 mg, 0.984 mmol) in DCM (2 ml) was added TFA (2 ml) and theresulting solution stirred at room temperature for 3 hrs. The solutionwas then diluted with DCM (5 ml) and washed with sat. sodium bicarbonatesolution until the washings were basic. The organic layer was then dried(MgSO₄), filtered and evaporated to dryness to yield the desired product7(ii) as a white solid (236 mg, 94%).

¹H NMR (500 MHz, CDCl₃) δ 0.86, d, J=6.8 Hz, 3H, 0.88, d, J=6.8 Hz, 3H,1.45, m, 1H, 1.57, m, 1H, 1.74, m, 1H, 2.64, s, NH₂; 3.54, m, 1H, 5.20,s, 2H, 7.22, m, 2H, 7.35, m, 2H. MS (ES +ve) m/z 256.1 (100%) [M+H]⁺.

This compound was prepared in two steps. The first step via Protocol 1,using 7(ii) (230 mg, 0.900 mmol) and Fmoc-(D)-arg(Pmc)-OH (563 mg, 0.850mmol) to yield the Fmoc protected precursor 7(iii) as a white foamysolid (662 mg, MS (ES +ve) m/z 900 (100%) [M+H]⁺). The desired productwas then prepared via Protocol 2, using the precursor 7(iii) (200 mg,0.22 mmol) to afford the product 7(iv) as a white solid (135 mg, 66% twosteps).

¹H NMR (500 MHz, CDCl₃) δ 0.81, d, J=5.9 Hz, 3H, 0.83, d, J=5.9 Hz, 3H,1.21, s, 6H, 1.51, m, 5H, 1.71, m, 3H, 2.01, s, 3H, 2.01, m, 1H, 2.47,s, 3H, 2.49, s, 3H, 2.53, m, 2H, 3.08, m, 2H, 3.33, m, 1H, 4.46, m, 1H,5.10, ABq, J=12.9 Hz, 1H, 5.15, ABq, J=12.9 Hz, 1H, 6.34, br s, NH;7.16, m, 2H, 7.30, m, 2H, 7.75, d, J=7.8 Hz, NH. MS (ES +ve) m/z 678.0(100%) [M+H]⁺.

This compound was prepared via Protocol 1, using 6(vi) (111 mg, 0.169mmol) and 7(iv) (130 mg, 0.179 mmol) to yield 7(v) as a white solid (172mg, 78%).

¹H NMR (500 MHz, CDCl₃) δ 0.38, d, J=6.2 Hz, 3H, 0.43, d, J=6.6 Hz, 3H,0.70, m, 2H, 0.81, d, J=5.5 Hz, 3H, 0.82, d, J=5.5 Hz, 3H, 0.89, m, 1H,1.12, m, 6H, 1.19, s, 6H, 1.29, m, 2H, 1.33, s, 9H, 1.58, m, 4H, 1.68,m, 2H, 1.71, m, 1H, 2.00, s, 3H, 2.46, s, 3H, 2.48, s, 3H, 2.50, m, 2H,2.81, m, 2H, 3.07, m, 2H, 3.78, m, 1H, 3.96, m, 2H, 4.33, m, 2H, 4.46,m, 3H, 4.73, m, NH; 5.11, ABq, J=12.7 Hz, 1H, 5.19, ABq, J=12.7 Hz, 1H,6.12, d, J=7.3 Hz, NH; 6.23, br s, NH; 7.26, m, 11H, 7.36, d, J=10.0 Hz,1H, 7.75, d, J=8.0 Hz, 1H, 7.77, d, J=8.3 Hz, 1H, 7.84, d, J=9.0 Hz, 1H,7.85, d, J=9.0 Hz, 1H. MS (ES +ve) m/z 1301.9 (100%) [M+H]⁺; 601.7 (60)[M+2H-BOC]²⁺.

This compound was prepared via Protocol 3, using 7(v) (160 mg, 0.123mmol) to yield 7 as an off white solid (109 mg, 88%).

¹H NMR (300 MHz, CD₃OD) δ 0.51, d, J=6.4 Hz, 3H, 0.56, d, J=6.4 Hz, 3H,0.90, d, J=5.7 Hz, 3H, 0.95, d, J=5.7 Hz, 3H, 1.15, m, 2H, 1.25, m, 3H,1.67, m, 111H, 2.82, m, 2H, 3.16, m, 2H, 3.97, m, 1H, 4.15, m, 2H, 4.34,m, 1H, 4.48, m, 3H, 5.21, ABq, J=12.8 Hz, 1H, 5.28, ABq, J=12.8 Hz, 1H,7.05, d, J=4.5 Hz, 1H, 7.08, d, J=4.5 Hz, 1H, 7.20, m, 2H, 7.32, m, 4H,7.44, m, 3H, 7.54, d, J=9.0 Hz, 1H, 7.89, d, J=8.1 Hz, 1H, 7.91, d,J=7.7 Hz, 1H, 8.01, d, J=9.0 Hz, 1H, 8.02, d, J=9.0 Hz, 1H. MS (ES +ve)m/z 935.7 (5%) [M+H]⁺; 468.7 (100) [M+2H]²⁺.

Synthesis of Compound 8

To BOC-(L)-leu-OH (250 mg, 1.08 mmol) and potassium carbonate (100 mg,7.24 mmol) in acetone (25 ml) was added 2,6-dichlorobenzyl bromide (266mg, 1.50 mmol). The resulting solution was heated at reflux overnightbefore being cooled, filtered and evaporated to dryness. The resultantresidue was subjected to flash column chromatography over silica,eluting with 5% ethyl acetate/hexane to first remove 2,6-dichlorobenzylbromide, then with DCM to yield the product 8(i) as a white solid (383mg, 91%).

¹H NMR (500 MHz, CDCl₃) δ 0.85, d, J=7.8 Hz, 6H, 1.37, s, 9H, 1.46, m,1H, 1.58, m, 1H, 1.68, m, 1H, 4.40, m, 1H, 5.99, d, J=7.8 Hz, NH; 5.35,s, 2H, 7.18, dist t, 1H, 7.27, d, J=8.3 Hz, 2H. MS (ES +ve) m/z 333.2(100%) [M+H-C₄H₈]⁺; 289.9 (50) [M+H-BOC]⁺.

To 8(i) (380 mg, 0.974 mmol) in DCM (2 ml) was added TFA (2 ml) and theresulting solution stirred at room temperature for 1 hr. The solutionwas then diluted with ethyl acetate (20 ml) and washed with sat. sodiumbicarbonate solution added until the washings were basic. The organiclayer was then separated and the aqueous layer extracted once more withethyl acetate (10 ml). The combined organic layers were dried (MgSO₄),filtered and evaporated to dryness to yield the desired product 8(ii) asa white solid (275 mg, 97%).

¹H NMR (500 MHz, CDCl₃) δ 0.84, d, J=7.0 Hz, 3H, 0.86, d, J=8.0 Hz, 3H,1.48, m, 1H, 1.57, m, 1H, 1.73, m, 1H, 3.58, m, 1H, 3.76, s, NH₂; 5.35,ABq, J=11.8 Hz, 1H, 5.38, ABq, J=11.8 Hz, 1H, 7.19, dist t, 1H, 7.29, d,J=7.9 Hz, 2H. MS (ES +ve) m/z 290 (100%) [M+H]⁺.

This compound was prepared in two steps. The first step via Protocol 1,using 8(ii) (120 mg, 0.41 mmol) and Fmoc-(D)-arg(Pbf)-OH (260 mg, 0.40mmol) to yield the Fmoc protected precursor 8(iii) as a white foamysolid (MS (ES +ve) m/z 900 (100%) [M+H]⁺). This was then deprotected viaProtocol 2 to afford the desired compound 8(iv) as a white solid (178mg, 64% two steps).

¹H NMR (300 MHz, CDCl₃) δ 0.81, d, J=5.9 Hz, 3H, 0.83, d, J=5.9 Hz, 3H,1.21, s, 6H, 1.51, m, 5H, 1.71, m, 3H, 2.01, s, 3H, 2.02, m, 1H, 2.47,s, 3H, 2.49, s, 3H, 2.53, m, 2H, 3.08, m, 2H, 3.33, m, 1H, 4.46, m, 1H,5.10, ABq, J=12.9 Hz, 1H, 5.15, ABq, J=12.9 Hz, 1H, 6.34, br s, NH;7.16, m, 2H, 7.30, m, 2H, 7.75, d, J=7.8 Hz, NH. MS (ES +ve) m/z 678(100%) [M+H]⁺.

This compound was prepared via Protocol 1, using 6(vi) (160 mg, 0.25mmol) and 8(iv) (175 mg, 0.25 mmol) to yield 8(v) as a white solid (231mg, 69%).

¹H NMR (300 MHz, CDCl₃) δ 0.46, d, J=6.2 Hz, 3H, 0.52, d, J=6.5 Hz, 3H,0.79, m, 2H, 0.86, d, J=6.7 Hz, 3H, 0.88, d, J=6.7 Hz, 3H, 0.94, m, 1H,1.19, m, 6H, 1.41, s, 6H, 1.43, s, 9H, 1.64, m, 5H, 1.83, m, 2H, 2.07,s, 3H, 2.51, s, 3H, 2.58, s, 3H, 2.92, s, 2H, 3.08, m, 2H, 3.16, m, 2H,3.88, m, 1H, 4.05, m, 2H, 4.48, m, 5H, 4.86, m, NH; 5.37, ABq, J=11.9Hz, 1H, 5.44, ABq, J=11.9 Hz, 1H, 6.20, d, J=7.0 Hz, NH; 6.32, br s, NH;7.25, m, 10H, 7.47, d, J=9.1 Hz, 1H, 7.85, d, J=7.9 Hz, 2H, 7.95, d,J=9.4 Hz, 1H, 7.98, d, J=9.7 Hz, 1H. MS (ES +ve) m/z 1322.3 (60%)[M+H]⁺; 612.8 (100) [M+2H-BOC]²⁺.

This compound was prepared via Protocol 3, using 8(v) (185 mg, 0.138mmol) to yield 8 as a white solid (78 mg, 98%).

¹H NMR (300 MHz, CD₃OD) δ 0.50, d, J=6.3 Hz, 3H, 0.56, d, J=6.4 Hz, 3H,0.87, d, J=5.2 Hz, 3H, 0.92, d, J=5.2 Hz, 3H, 0.99, m, 2H, 1.23, m, 4H,1.66, m, 10H, 2.86, m, 2H, 3.19, m, 2H, 3.96, m, 1H, 4.16, m, 2H, 4.49,m, 4H, 5.38, ABq, J=11.7 Hz, 1H, 5.44, ABq, J=11.7 Hz, 1H, 7.10, m, 2H,7.17, m, 2H, 7.32, m, 3H, 7.39, m, 2H, 7.46, d, J=9.0 Hz, 1H, 7.57, d,J=9.0 Hz, 1H, 7.87, d, J=8.1 Hz, 1H, 7.93, d, J=8.1 Hz, 1H, 7.99, d,J=9.0 Hz, 1H, 8.04, d, J=9.0 Hz, 1H. MS (ES +ve) m/z 969.8 (10%) [M+H]⁺;485.7 (100) [M+2H]²⁺.

Synthesis of Compound 9

To BOC-(L)-Leu-OH (250 mg, 1.08 mmol) and potassium carbonate (747 mg,5.40 mmol) in acetone (50 mL) was added 4-methylbenzyl bromide (300 mg,1.62 mmol). The resulting solution was heated at reflux overnight beforebeing cooled, filtered and evaporated to dryness. The resultant residuewas subjected to flash column chromatography over silica, eluting with1:4 hexane/DCM to first remove 4-chlorobenzyl bromide, then with DCM toyield the product 9(i) as a colourless oil (340 mg, 94%).

¹H NMR (300 MHz, CDCl₃) δ 0.91, d, J=6.5 Hz, 3H, 0.92, d, J=6.2 Hz, 3H,1.43, s, 9H, 1.49, m, 2H, 1.66, m, 1H, 2.35, s, 3H, 4.35, m, 1H, 4.95,d, J=9.2 Hz, NH; 5.08, ABq, J=12.3 Hz, 1H, 5.14, ABq, J=12.3 Hz, 1H;7.16, ABq, J=7.9 Hz, 2H, 7.24, ABq, J=7.9 Hz, 2H. MS (ES +ve) m/z 353.3(100%) [M+H₂O]⁺; 336.3 (90) [M+H]⁺.

To 9(i) (340 mg, 1.01 mmol) in DCM (2 mL) was added TFA (2 mL) and theresulting solution stirred at room temperature for 3 hrs. The solutionwas then diluted with DCM (5 mL) and washed with sat. sodium bicarbonatesolution until the washings were basic. The organic layer was then dried(MgSO₄), filtered and evaporated to dryness to yield the desired product9(ii) as a white solid (215 mg, 90%).

¹H NMR (300 MHz, CDCl₃) δ 0.90, d, J=6.5 Hz, 3H, 0.92, d, J=6.7 Hz, 3H,1.43, m, 1H, 1.55, m, 1H/NH₂; 1.76, m, 1H, 2.35, s, 3H, 3.49, m, 1H,5.10, s, 2H, 7.18, ABq, J=7.9 Hz, 2H, 7.25, ABq, J=7.9 Hz, 2H. MS (ES+ve) m/z 236.0 (100%) [M+H]⁺.

This compound was prepared via Protocol 1 using 9(ii) (215 mg, 0.914mmol) and Fmoc-(D)-arg(Pmc)-OH (606 mg, 0.914 mmol) to yield the desiredproduct 9(iii) as an off white solid (780 mg, 97%).

¹H NMR (500 MHz, CDCl₃) δ 0.78, m, 6H, 1.28, s, 6H, 1.61, m, 8H, 1.91,m, 1H, 2.01, s, 3H, 2.26, s, 3H, 2.50, m, 2H, 2.54, s, 3H, 2.57, s, 3H,3.23, m, 2H, 4.03, m, 1H, 4.25, m, 3H, 4.52, m, 1H, 4.97, ABq, J=12.2Hz, 1H, 5.03, ABq, J=12.2 Hz, 1H, 6.42, br s, NH; 7.06, ABq, J=7.7, Hz,2H, 7.13, ABq, J=7.7, Hz, 2H, 7.17, m, 2H, 7.31, dd, J₁=7.5 Hz, J₂=7.5Hz, 2H, 7.51, m, 2H, 7.68, d, J=7.5 Hz, 2H. MS (ES +ve) m/z 658.1 (100%)[M+H-Fmoc]⁺.

This compound was prepared via Protocol 2, using 9(iii) (650 mg, 0.739mmol) to yield the desired product 9(iv) as a colourless oil (409 mg,84%).

¹H NMR (500 MHz, CDCl₃) δ 0.86, d, J=5.9 Hz, 3H, 0.88, d, J=5.4 Hz, 3H,1.28, s, 6H, 1.58, m, 5H/NH₂; 1.77, m, 3H, 2.00, m, 1H, 2.09, s, 3H,2.31, s, 3H, 2.54, s, 3H, 2.56, s, 3H, 2.59, m, 2H, 3.15, m, 2H, 3.40,m, 1H, 4.49, m, 1H, 5.01, ABq, J=12.2 Hz, 1H, 5.08, ABq, J=12.2 Hz, 1H,6.42, br s, NH; 7.11, ABq, J=8.0, Hz, 2H, 7.18, ABq, J=8.0, Hz, 2H,7.81, d, J=7.8 Hz, NH. MS (ES +ve) m/z 658.1 (100%) [M+H]⁺.

This compound was prepared via Protocol 1, using 9(iv) (377 mg, 0.573mmol) and Fmoc-(D)-lys(BOC)-OH (268 mg, 0.573 mmol) to yield the desiredproduct 9(v) as an off white solid (575 mg, 91%).

¹H NMR (500 MHz, CDCl₃) δ 0.82, m, 6H, 1.19, s, 6H, 1.39, s, 9H, 1.58,m, 13H, 2.02, s, 3H, 2.28, s, 3H, 2.49, m, 2H, 2.53, s, 3H, 2.55, s, 3H,3.02, m, 2H, 3.19, m, 2H, 3.93, m, 1H, 4.19, m, 2H, 4.25, m, 1H, 4.53,m, 2H, 4.98, m, 2H, 6.23, m, NH; 6.50, br s, NH; 7.07, m, 2H, 7.11, m,2H, 7.22, m, 2H, 7.33, m, 2H, 7.53, m, 2H, 7.68, m, 2H. MS (ES +ve) m/z1108.3 (100%) [M+H]⁺.

This compound was prepared via Protocol 2, using 9(v) (290 mg, 0.262mmol) to yield the desired product 9(vi) as an off white solid (162 mg,70%).

¹H NMR (500 MHz, CDCl₃) δ 0.85, d, J=6.3 Hz, 3H, 0.87, d, J=6.3 Hz, 3H,1.29, s, 6H, 1.40, s, 9H, 1.58, m, 10H/NH₂; 1.78, dist t, 2H, 1.89, m,1H, 2.09, s, 3H, 2.32, s, 3H, 2.54, s, 3H, 2.56, s, 3H, 2.61, m, 2H,3.05, m, 2H, 3.22, m, 2H, 3.36, m, 1H, 4.54, m, 2H, 4.95, m, NH; 5.01,ABq, J=12.2 Hz, 1H, 5.07, ABq, J=12.2 Hz, 1H, 6.42, br s, NH; 7.12, ABq,J=7.8 Hz, 2H, 7.18, ABq, J=7.8 Hz, 2H, 7.60, d, J=7.3 Hz, NH; 8.00, d,J=6.4 Hz, NH. MS (ES +ve) m/z 886.3 (100%) [M+H]⁺.

This compound was prepared via Protocol 1, using 1(ii) (75 mg, 0.181mmol) and 9(vi) (160 mg, 0.181 mmol) to yield the desired product 9(vii)as a white solid (193 mg, 83%).

¹H NMR (500 MHz, CDCl₃) δ 0.47, d, J=6.5 Hz, 3H, 0.53, d, J=6.5 Hz, 3H,0.78, m, 1H, 0.87, d, J=5.8 Hz, 3H, 0.89, d, J=5.8 Hz, 3H, 0.91, m, 1H,1.22, m, 8H, 1.28, s, 6H, 1.42, s, 9H, 1.62, m, 3H, 1.76, dist t, 2H,1.82, m, 1H, 2.09, s, 3H, 2.33, s, 3H, 2.55, s, 3H, 2.57, s, 3H, 2.59,m, 2H, 2.91, m, 2H, 3.16, m, 2H, 3.88, m, 1H, 4.05, m, 2H, 4.49, m, 4H,4.84, m, NH; 5.04, ABq, J=12.2 Hz, 1H, 5.13, ABq, J=12.2 Hz, 1H, 6.19,d, J=6.4 Hz, NH; 6.27, s, NH; 7.22, m, 11H, 7.46, d, J=9.1 Hz, 1H, 7.85,dist t, 2H, 7.94, dist t, 2H. MS (ES +ve) m/z 1282 (100%) [M+H]⁺.

This compound was prepared via Protocol 3, using 9(vii) (107 mg, 0.083mmol) to yield the product 9 as a white solid (28 mg, 34%).

¹H NMR (300 MHz, CD₃OD) δ 0.38, δ, J=6.2 Hz, 3H, 0.43, d, J=6.2 Hz, 3H,0.85, m, 8H, 1.07, m, 2H, 1.18, m, 2H, 1.59, m, 9H, 2.25, s, 3H, 2.74,m, 2H, 3.09, m, 2H, 3.90, m, 1H, 4.06, m, 2H, 4.34, m, 3H, 4.40, ABq,J=14.7 Hz, 1H, 4.51, ABq, J=14.7 Hz, 1H, 4.99, ABq, J=12.1 Hz, 1H, 5.05,ABq, J=12.1 Hz, 1H, 6.99, d, J=8.5 Hz, 1H, 7.01, d, J=8.5 Hz, 1H, 7.09,d, J=7.8 Hz, 1H, 7.15, m, 4H, 7.27, m, 3H, 7.41, d, J=9.0 Hz, 1H, 7.49,dd, J₁=9.1 Hz, J₂=11.6 Hz, 1H, 7.84, m, 2H, 7.95, m, 2H. MS (ES +ve) m/z916 (5%) [M+H]⁺; 812 (10) [M+H-pMeBz]⁺; 459 (95) [M+2H]²⁺; 407 (100)[M+2H-pMeBz]²⁺.

Synthesis of Compound 10

This compound was prepared via Protocol 1, using (R)-1(ii) (67 mg, 0.162mmol) and 1(viii) (140 mg, 0.161 mmol) to yield the desired product10(i) as a white solid (108 mg, 53%).

¹H NMR (300 MHz, CDCl₃) δ 0.51, d, J=6.3 Hz, 3H, 0.56, d, J=6.3 Hz, 3H,0.84, d, J=5.4 Hz, 3H, 0.86, m, 3H, 0.88, d, J=5.4 Hz, 3H, 1.21, m, 6H,1.25, s, 6H, 1.29, m, 2H, 1.43, s, 9H, 1.64, m, 4H, 1.76, m, 2H, 1.84,m, 1H, 2.09, s, 3H, 2.52, s, 3H, 2.54, s, 3H, 2.58, m, 2H, 2.94, m, 2H,3.11, m, 2H, 3.89, m, 1H, 3.99, m, 2H, 4.35, m, 1H, 4.37, ABq, J=14.7Hz, 1H, 4.90, m, 1H, 4.58, ABq, J=14.7 Hz, 1H, 4.90, m, NH; 5.04, ABq,J=12.3 Hz, 1H, 5.13, ABq, J=12.3 Hz, 1H, 6.10, br s NH; 6.19, br s, NH;7.45, m, 12H, 7.44, d, J=9.3 Hz, 1H, 7.82, d, J=8.3 Hz, 1H, 7.84, d,J=8.3 Hz, 1H, 7.89, d, J=8.8 Hz, 1H, 7.94, d, J=8.8 Hz, 1H. MS (ES +ve)m/z 1268 (50%) [M+H]⁺; 585 (100) [M+2H-BOC]²⁺.

This compound was prepared via Protocol 3, using 10(i) (105 mg, 0.083mmol) to yield an impure product. Protocol 3 was repeated on 80 mg ofthis product to yield 10 as an off white solid (58 mg, 82%).

¹H NMR (300 MHz, CD₃OD) δ 0.41, d, J=6.6 Hz, 3H, 0.46, d, J=6.6 Hz, 3H,0.78, d, J=5.7 Hz, 3H, 0.83, d, J=5.7 Hz, 3H, 1.06, m, 6H, 1.38, m, 1H,1.53, m, 8H, 1.72, m, 1H, 2.78, m, 2H, 3.05, m, 2H, 3.84, m, 1H, 3.97,m, 1H, 4.02, m, 1H, 4.25, m, 1H, 4.35, m, 2H, 4.51, ABq, J=15.0 Hz, 1H,5.00, ABq, J=12.3 Hz, 1H, 5.05, ABq, J=12.3 Hz, 1H, 6.96, d, J=8.7 Hz,1H, 7.05, d, J=8.4 Hz, 1H, 7.13, m, 2H, 7.24, m, 7H, 7.38, d, J=9.0 Hz,1H; 7.45, d, J=9.0 Hz, 1H, 7.80, d, J=8.1 Hz, 1H, 7.84, d, J=7.8 Hz, 1H,7.91, d, J=9.0 Hz, 1H, 7.96, d, J=8.7 Hz, 1H. MS (ES +ve) m/z 902 (10%)[M+H]⁺; 452.0 (100) [M+H]²⁺.

Synthesis of Compound 11

To a solution of 1,1′-biphen-2,2′-diol (0.21 g, 1.15 mmol) in dryacetone (25 ml) was added potassium carbonate (1.62 g, 12.0 mmol). Tothe resulting suspension a solution of 1-bromo-3-methylbutane (0.18 ml,1.50 mmol) in dry acetone (10 ml) was added portionwise over 90 minutes.The reaction mixture was then heated at reflux for 18 hours. The cooledmixture was filtered and the solid residue was washed with acetone (2×20ml). The combined filtrate and washes were concentrated in vacuo toyield the product 11(i) as a colourless oil (292 mg, 99%).

¹H NMR (300 MHz, CDCl₃) δ 0.95, d, J=6.2 Hz, 6H, 1.71, m, 3H, 4.13, t,J=6.4 Hz, 2H, 7.25, m, 8H. MS (EI) m/z 256 (30%) [M]⁺; 186 (100)[M-(CH₂CH₂CH(CH₃)₂)]⁺.

To a solution of 11(i) (0.29 g, 1.13 mmol) in methanol (20 ml) was addedpotassium carbonate (1.83 g, 13.2 mmol) and bromoacetic acid (0.56 g,4.03 mmol) and the resulting suspension was heated at reflux for 16hours. The cooled reaction mixture was concentrated in vacuo and theresidue was dissolved in distilled water (100 ml) then washed with ether(3×20 ml). The aqueous solution was acidified (10% HCl) and extractedwith DCM (3×20 ml). The combined organic layers were dried (MgSO₄) andconcentrated in vacuo to yield the title compound 11(ii) as a thickcolourless oil (111 mg, 30%).

¹H NMR (300 MHz, CDCl₃) δ 0.77, d, J=4.4 Hz, 6H, 1.45, m, 3H, 3.99, t,J=6.5 Hz, 2H, 4.62, s, 2H, 6.87, dd, J=8.2, 0.9 Hz, 1H, 7.08, m, 3H,7.31, m, 4H. MS (ES +ve) m/z 353 (12%) [M+K]⁺; 337 (39) [M+Na]⁺; 332(96) [M+NH₄]⁺; 315 (100) [M+H]⁺; 245 (38).

This compound was prepared via Protocol 1, using (R)-Lysine(Boc)-methylester (0.10 g, 0.38 mmol) and 11(ii) (0.11 g, 0.34 mmol) in anhydrousacetonitrile (10 ml) with EDCI (0.09 g, 0.45 mmol) and HObt (0.08 g,0.58 mmol). Purification with 1-2% methanol:DCM gave product 11(iii) asa pale yellow oil (179 mg, 93%).

¹H NMR (300 MHz, CDCl₃) δ 0.76, dd, J=6.4 Hz, 6H, 1.08, m, 2H, 1.43, m,12H, 1.67, m, 2H, 3.00, m, 3H, 3.66, s, 3H, 3.90, m, 3H, 4.44, m, 4H,6.74, br d, J=8.5 Hz, 1H, 8.86, d, J=7.9 Hz, 1H, 7.03, m, 3H, 7.27, m,4H. MS (ES +ve) m/z 579 (11%) [M+Na]⁺; 557 (100) [M+H]⁺; 457 (29)[M-Boc+H]⁺; 233 (88).

To a solution of 11(iii) (0.18 g, 0.32 mmol) in THF:water (4:1) (15 ml)was added lithium hydroxide (0.11 g, 2.60 mmol) and the resultingsolution was stirred at 20° C. for 16 hours. The reaction mixture wasdiluted with water (5 ml), acidified with 10% HCl and extracted with DCM(4×10 ml). The combined organic layers were dried (MgSO₄) andconcentrated in vacuo to give the product 11(iv) as a pale yellow oil(108 mg, 62%).

¹H NMR (500 MHz, CDCl₃) δ 0.77, dd, J=6.3, 4.4 Hz, 6H, 1.13, m, 2H,1.44, m, 14H, 1.75, br s, 1H, 3.12, m, 2H, 3.94, m, 2H, 4.49, ABq,J=14.6 Hz, 2H, 4.64, m, 1H, 6.87, m, 2H, 6.99, m, 2H, 7.05, t, J=7.8 Hz,1H, 7.26, m, 4H. MS (ES +ve) m/z 543, (100%) [M+H]⁺; 487 (46) [M+H-56]⁺;443 (46) [M+H-Boc]⁺.

This compound was prepared in two steps. The first step via Protocol 1,using 1(iv) (1.12 g, 5.06 mmol) and Fmoc-(D)-arg(Pbf)-OH (3.06 mg, 4.72mmol) to yield the Fmoc protected precursor 11(v) as a white foamy solid(MS (ES +ve) m/z 852 (100%) [M+H]⁺). This was then deprotected viaProtocol 2 to afford the desired compound 11(vi) as a yellow oil (1.54g, 52% two steps).

MS (ES +ve) m/z 630 (100%) [M+H]⁺

This compound was prepared via Protocol 1, using 11(iv) (70 mg, 0.13mmol) and 11(vi) (77 mg, 0.12 mmol) in anhydrous acetonitrile with EDCI(40 mg, 0.21 mmol) and HObt (39 mg, 0.29 mmol). Purification with 1-2%methanol:DCM gave product 11(vii) as a clear colourless oil (103 mg,71%).

¹H NMR (300 MHz, CDCl₃) δ 0.77, dd, J=6.4, 1.8 Hz, 6H, 0.88, dd, J=7.3,7.3 Hz, 6H, 1.08, m, 2H, 1.43, m, 23H, 1.63, m, 5H, 1.83, m, 1H, 2.05,s, 3H, 2.47, s, 3H, 2.54, s, 3H, 2.91, s, 2H, 3.00, m, 2H, 3.17, m, 2H,3.93, m, 2H, 4.46, m, 5H, 4.85, m, 1H, 5.14, ABq, J=12.3 Hz, 2H, 6.15,br s, 2H, 6.79, m, 2H, 7.01, m, 3H, 7.28, m, 10H, 7.61, br d, 1H. MS (ES+ve) m/z 1153 (100%) [M+H]⁺; 527 (68); 288 (98).

This compound was prepared via Protocol 3, using 11(vii) (95 mg, 82μmol) and TFA:TIPS:H₂O (95:2.5:2.5) (2 ml). Precipitation from methanolusing ether (3 times) gave the product 11 as off-white crystals (67 mg,93%).

¹H NMR (300 MHz, CD₃OD) δ 0.78, dd, J=6.4, 1.2 Hz, 6H, 0.91, dd, J=14.4,5.6 Hz, 6H, 1.25, m, 2H, 1.55, m, 14H, 2.89, m, 2H, 3.16, m, 2H, 3.96,m, 2H, 4.44, m, 5H, 5.14, ABq, J=10.7 Hz, 2H, 7.02, m, 4H, 7.23, m, 2H,7.35, m, 7H. MS (ES +ve) m/z 802 (4%) [M+H]⁺; 401 (100) [M+H]²⁺.

Synthesis of Compound 12

To BOC(L)-Leu-OH (300 mg, 1.30 mmol) and potassium carbonate (0.4 g,2.90 mmol) in acetone (25 ml) was added 4-bromo-1-methylbutane (0.2 ml,1.60 mmol). The resulting solution was heated at reflux overnight beforebeing cooled, filtered and evaporated to dryness. The resultant residuewas subjected to flash column chromatography over silica, eluting withDCM to yield the product 12(i) as a colourless oil (172 mg, 44%).

¹H NMR (300 MHz, CDCl₃) δ 0.94, m, 12H, 1.44, s, 9H, 1.55, m, 4H, 1.70,m, 2H, 4.14, dt, J=6.8 Hz, J₂=2.0 Hz, 2H. 4.29, m, 1H, 5.04, d, J=8.3Hz, NH. MS (ES +ve) m/z 302.1 (100%) [M+H]⁺; 246.1 (70) [M+H-iBu]⁺;202.1 (70) [M+H-BOC]⁺.

To 12(i) (170 mg, 0.592 mmol) in DCM (2 ml) was added TFA (2 ml) and theresulting solution stirred at room temperature for 1 hr. The solutionwas then diluted with ethyl acetate (10 ml) and washed with sat. sodiumbicarbonate solution until the washings were basic. The organic layerwas then dried (MgSO₄), filtered and evaporated to dryness to yield thedesired product 12(ii) as a white solid (93 mg, 78%).

¹H NMR (300 MHz, CDCl₃) δ 0.93, m, 12H, 1.43, m, 1H, 1.55, m, 3H/NH₂;1.73, m, 2H, 3.45, dd, J₁=8.2 Hz, J₂=5.9 Hz, 1H, 4.14, t, J=6.9 Hz, 2H.MS (ES +ve) m/z 202.0 (100%) [M+H]⁺.

This compound was prepared via Protocol 1 using 12(ii) (90 mg, 0.481mmol) and Fmoc-(D)-arg(Pmc)-OH (160 mg, 0.241 mmol) to yield the desiredproduct 12(iii) as an off white solid (198 mg, 97%).

¹H NMR (300 MHz, CDCl₃) δ 0.84, m, 12H, 1.21, s, 3H, 1.22, s, 3H, 1.47,m, 2H, 1.60, m, 9H, 1.90, m, 1H, 2.05, s, 3H, 2.51, m, 2H, 2.55, s, 3H,2.58, s, 3H, 3.24, m, 2H, 4.05, m, 3H, 4.24, m, 3H, 4.47, m, 1H, 6.26,br s, NH; 6.35, d, J=8.0 Hz, NH; 6.40, br s, NH; 7.18, t, J=7.4 Hz, 2H,7.32, t, J=7.5 Hz, 2H, 7.37, d, J=7.7 Hz, NH; 7.51, d, J=7.4 Hz, 2H,7.69, d, J=7.5 Hz, 2H. MS (ES +ve) m/z 846.0 (100%) [M+H]⁺.

This compound was prepared via Protocol 2, using 12(iii) (150 mg, 0.177mmol) to yield the desired product 12(iv) as a colourless oil (101 mg,91%).

¹H NMR (300 MHz, CDCl₃) δ 0.92, m, 12H, 1.30, s, 6H, 1.52, m, 3H, 1.62,m, 4HJNH₂; 1.80, m, 5H, 2.10, s, 3H; 2.55, s, 3H, 2.57, s, 3H, 2.62, t,J=6.7 Hz, 2H, 3.19, m, 2H, 3.40, m, 1H, 4.11, m, 2H, 4.46, m, H, 6.31,br s, NH; 6.38, br s, NH; 7.76, d, J=8.0 Hz, NH. MS (ES +ve) m/z 624.0(100%) [M+H]⁺.

This compound was prepared via Protocol 1, using 6(vi) (75 mg, 0.117mmol) and 12(iv) (86 mg, 0.138 mmol) to yield 12(v) as a light brownsolid (122 mg, 84%).

¹H NMR (300 MHz, CDCl₃) δ 0.47, d, J=6.6 Hz, 3H, 0.52, d, J=6.6 Hz, 3H,0.76, m, 2H, 0.91, m, 12H, 1.18, m, 6H, 1.27, s, 6H, 1.41, s, 9H, 1.53,m, 5H, 1.63, m, 5H, 1.77, m, 3H, 2.09, s, 3H, 2.55, s, 3H, 2.57, s, 3H,2.60, m, 2H, 2.92, m, 2H, 3.19, m, 2H, 3.89, m, 1H, 4.11, m, 4H, 4.43,m, 4H, 4.84, m, NH; 6.19, d, J=7.7 Hz, NH; 6.28, br s, NH; 7.26, m, 7H,7.46, d, J=9.2 Hz, 1H, 7.84, d, J=8.9 Hz, 1H, 7.86, d, J=8.8 Hz, 1H,7.93, d, J=9.3 Hz, 1H, 7.96, d, J=9.5 Hz, 1H. MS (ES +ve) m/z 1247.9(40%) [M+H]⁺; 574.7 (100) [M+2H-BOC]²⁺.

This compound was prepared via Protocol 3, using 12(v) (120 mg, 0.096mmol) to yield 12 as an off white solid (84 mg, 92%).

¹H NMR (300 MHz, CD₃OD) δ 0.52, d, J=6.6 Hz, 3H, 0.57, d, J=6.6 Hz, 3H,0.91, m, 14H, 1.14, m, 2H, 1.26, m, 2H, 1.54, m, 5H, 1.65, m, 7H, 1.84,m, 1H, 2.82, m, 2H, 3.18, m, 2H, 3.95, m, 1H, 4.14, m, 4H, 4.36, m, 2H,4.46, ABq, J=14.6 Hz, 1H, 4.58, ABq, J=14.6 Hz, 1H, 7.07, dist t, 2H,7.21, dist t, 2H, 7.34, dist t, 2H, 7.47, d, J=9.3 Hz, 1H, 7.56, d,J=9.3 Hz, 1H, 7.91, dist t, 2H, 8.03, dist t, 2H. MS (ES +ve) m/z 882.0(5%) [M+H]⁺; 441.6 (100) [M+2H]²⁺.

Synthesis of Compound 13

To BOC-(L)-Leu-OH (200 mg, 0.865 mmol) and potassium carbonate (400 mg,2.89 mmol) in acetone (40 ml) was added (2-bromoethyl)benzene (0.14 ml,1 mmol). The resulting solution was heated at reflux overnight beforebeing cooled, filtered and evaporated to dryness. The resultant residuewas subjected to flash column chromatography over silica, eluting with5% ethyl acetate/hexane to first remove (2-bromoethyl)benzene, then withDCM to yield the product 13(i) as a colourless oil (235 mg, 81%).

¹H NMR (500 MHz, CDCl₃) δ 0.86, d, J=6.6 Hz, 3H, 0.88, d, J=6.6 Hz, 3H,1.42, s, 9H, 1.47, m, 2H, 1.54, m, 1H, 2.92, t, J=7.0 Hz, 2H, 4.31, m,3H, 5.04, d, J=8.3 Hz, NH; 7.19, m, 3H, 7.26, m, 2H. MS (ES +ve) m/z374.2 (80%) [M+K]⁺; 358.3 (100) [M+Na]⁺; 336.3 (10) [M+H]⁺; 236.2 (50)[M+H-BOC]⁺.

To 13(i) (230 mg, 0.686 mmol) dissolved in DCM (2 ml) was added TFA (2ml) and the resulting solution stirred at room temperature for 2 hrs.Ethyl acetate (15 ml) was then added and the solution washed with sat.sodium bicarbonate solution until the washing were basic. The organiclayer was then dried (MgSO₄) and evaporated to dryness to yield thedesired product 13(ii) as a yellow oil (140 mg, 87%).

¹H NMR (500 MHz, CDCl₃) δ 0.87, d, J=5.7 Hz, 3H, 0.89, d, J=5.7 Hz, 3H,1.35, m, 1H, 1.48, m, 1H, 1.69, m, 1H, 1.89, m, NH₂; 2.94, t, J=7.0 Hz,2H, 3.42, dd, J=8.3 Hz, J₂=5.9 Hz, 1H, 4.33, m, 2H, 7.21, m, 3H, 7.28,m, 2H. MS (ES +ve) m/z 236.2 (100%) [M+H]⁺.

This compound was prepared in two steps. The first via Protocol 1, using13(ii) (92 mg, 0.391 mmol) and Fmoc-(D)-arg(Pmc)-OH (265 mg, 0.400 mmol)to yield the Fmoc protected precursor 13(iii) as a colourless oil (308mg, 90% MS (ES +ve) m/z 880.2 (100%) [M+H]⁺). The desired product wasthen prepared via Protocol 2, using 13(iii) (280 mg, 0.318 mmol) toafford the product 13(iv) as a colourless oil (123 mg, 59%).

¹H NMR (300 MHz, CDCl₃) δ 0.85, d, J=5.7 Hz, 3H, 0.86, d, J=5.9 Hz, 3H,1.29, s, 6H, 1.53, m, 4H/NH₂; 1.78, m, 5H, 2.09, s, 3H, 2.54, s, 3H,2.56, s, 3H, 2.60, m, 2H, 2.91, t, J=7.0 Hz, 2H, 3.17, m, 2H, 3.37, m,1H, 4.29, m, 2H, 4.43, m, 1H, 6.33, br s, NH; 6.38, br s, NH; 7.22, m,5H, 7.73, d, J=8.0 Hz, NH. MS (ES +ve) m/z 658.0 (100%) [M+H]⁺; 554.1(60) [M+H-EtPh]⁺.

This compound was prepared via Protocol 1, using 6(vi) (107 mg, 0.166mmol) and 13(iv) (107 mg, 0.167 mmol) to yield 13(v) as a white solid(118 mg, 55%).

¹H NMR (300 MHz, CDCl₃) δ 0.46, d, J=6.3 Hz, 3H, 0.51, d, J=6.3 Hz, 3H,0.77, m, 2H, 0.89, m, 6H; 1.19, m, 3H, 1.27, s, 6H, 1.41, s, 9H, 1.54,m, 5H, 1.76, m, 4H, 2.09, s, 3H, 2.54, s, 3H, 2.56, s, 3H, 2.61, m, 2H,2.91, m, 2H, 2.93, t, J=7.1 Hz; 3.15, m, 2H, 3.87, m, 1H, 4.04, m, 2H,4.42, m, 4H, 4.82, m, NH; 6.18, d, J=7.1 Hz, NH; 6.28, br s, NH; 7.21,m, 12H, 7.43, d, J=9.1 Hz, 1H, 7.83, d, J=7.8 Hz, 1H, 7.85, d, J=7.8 Hz,1H, 7.92, d, J=9.0 Hz, 1H, 7.93, d, J=8.9 Hz, 1H. MS (ES +ve) m/z 1282.0(80%) [M+H]⁺; 591.7 (100) [M+2H-BOC]²⁺.

This compound was prepared via Protocol 3, using 13(v) (110 mg, 0.086mmol) to yield 13 as a white solid (80 mg, 96%).

¹H NMR (300 MHz, CD₃OD) δ 0.50, d, J=6.2 Hz, 3H, 0.55, d, J=6.2 Hz, 3H,0.85, d, J=6.1 Hz, 3H, 0.89, d, J=6.1 Hz, 3H, 0.96, m, 2H, 1.16, m, 5H,1.57, m, 10H, 1.81, m, 1H, 2.80, m, 2H, 2.93, t, J=6.7 Hz, 2H, 3.16, m,2H, 3.94, m, 1H, 4.14, m, 2H, 4.34, m, 2H, 5.45, ABq, J=14.8 Hz, 1H,5.56, ABq, J=14.8 Hz, 1H, 7.04, d, J=4.3 Hz, 1H, 7.07, d, J=4.3 Hz, 1H,7.22, m, 9H, 7.45, d, J=9.0 Hz, 1H, 7.53, d, J=9.0 Hz, 1H, 7.88, d,J=7.6 Hz, 1H, 7.91, d, J=7.3 Hz, 1H, 7.99, d, J=9.0 Hz, 1H, 8.00, d,J=9.0 Hz, 1H. MS (ES +ve) m/z 915.9 (5%) [M+H]⁺; 458.9 (100) [M+2H]²⁺.

Synthesis of Compound 14

This compound was prepared via Protocol 1, using BOC-(L)-leu-OH (200 mg,0.865 mmol) and benzylamine (0.1 ml, 0.916 mmol) to yield the desiredproduct 14(i) as an off white solid (239 mg, 86%).

¹H NMR (500 MHz, CDCl₃) δ 0.86, d, J=6.8 Hz, 3H, 0.88, d, J=6.8 Hz, 3H,1.34, s, 9H, 1.53, m, 2H, 1.64, m, 1H, 4.30, m, 3H, 5.57, d, J=7.7 Hz,NH; 7.17, m, 5H, 7.50, m, NH. MS (ES +ve) m/z 359.2 (100%) [M+K]⁺; 343.3(20) [M+Na]⁺; 321.3 (20) [M+H]⁺; 222.3 (40) [M+H-BOC]⁺.

To 14(i) (230 mg, 0.719 mmol) dissolved in DCM (2 ml) was added TFA (2ml) and the resulting solution stirred at room temperature for 2 hrs.Ethyl acetate (15 ml) was then added and the solution washed with sat.sodium bicarbonate solution until the washing were basic. The organiclayer was then dried (MgSO₄) and evaporated to dryness to yield thedesired product 14(ii) as a colourless oil (65 mg, 41%).

¹H NMR (300 MHz, CDCl₃) δ 0.93, d, J=5.6 Hz, 3H, 0.96, d, J=5.6 Hz, 3H,1.37, m, 1H, 1.68, br s, NH₂; 1.73, m, 2H, 3.43, m, 1H, 4.42, d, J=5.8Hz, 2H, 7.27, m, 2H, 7.32, m, 3H, 7.69, m, NH. MS (ES +ve) m/z 221.2(100%) [M+H]⁺.

This compound was prepared in two steps. The first step via Protocol 1,using 14(ii) (60 mg, 0.272 mmol) and Fmoc-(D)-arg(Pmc)-OH (176 mg, 0.272mmol) to yield the Fmoc protected precursor 14(iii) as a white foamysolid (156 mg, 67%. MS (ES +ve) m/z 851.2 (100%) [M+H]⁺). The desiredproduct was then prepared via Protocol 2, using 14(iii) (156 mg, 0.183mmol) to afford the product 14(iv) as a white solid (85 mg, 74%).

¹H NMR (300 MHz, CDCl₃) δ 0.83, m, 6H, 1.44, s, 9H, 1.62, m, 6H/NH₂;1.80, m, 1H, 2.05, s, 3H, 2.43, s, 3H, 2.51, s, 3H, 2.90, s, 2H, 3.15,m, 2H, 3.62, m, 1H, 4.25, m, 2H, 4.45, m, 1H, 6.54, br s, NH; 7.14, m,5H, 7.72, dd, J₁=7.8 Hz, J₂=16.0 Hz, NH; 8.25, m, NH. MS (ES +ve) m/z629.0 (100%) [M+H]⁺.

This compound was prepared via Protocol 1, using 6(vi) (82 mg, 0.127mmol) and 14(iv)(80 mg, 0.127 mmol) to yield 14(v) as a white solid (63mg, 41%).

¹H NMR (300 MHz, CDCl₃) δ 0.44, d, J=6.5 Hz, 3H, 0.49, d, J=6.5 Hz, 3H,0.79, d, J=6.3 Hz, 3H, 0.83, d, J=6.3 Hz, 3H, 0.85, m, 2H, 1.11, m, 4H,1.26, m, 4H, 1.40, s, 6H, 1.43, s, 9H, 1.69, m, 5H, 1.95, m, 1H, 2.04,s, 3H, 2.46, s, 3H, 2.52, s, 3H, 2.90, s, 2H, 2.93, m, 2H, 3.19, m, 2H,3.80, m, 1H, 4.13, m, 2H, 4.30, m, 5H, 4.49, m, 1H, 5.05, m, NH; 5.04,ABq, J=12.2 Hz, 1H, 5.11, ABq, J=12.2 Hz, 1H, 6.19, d, J=6.8 Hz, NH;6.15, br s, NH; 6.46, br s, NH; 7.10, m, 6H, 7.31, m, 5H, 7.71, m, 3H,7.84, dist d, 1H, 7.90, d, J=9.2 Hz, 2H. MS (ES +ve) m/z 1252.9 (80%)[M+H]⁺; 577.4 (100) [M+2H-BOC]²⁺.

This compound was prepared via Protocol 3, using 14(v) (63 mg, 0.050mmol) to yield 14 as a white solid (40 mg, 82%).

¹H NMR (500 MHz, CD₃OD) δ 0.48, d, J=6.5 Hz, 3H, 0.53, d, J=6.5 Hz, 3H,0.90, m, 8H, 1.17, m, 5H, 1.36, m, 1H, 1.53, m, 3H, 1.68, m, 6H, 1.81,m, 1H, 2.77, m, 2H, 3.19, m, 2H, 3.87, m, 1H, 4.00, m, 1H, 4.10, m, 1H,4.21, m, 1H, 4.37, m, 3H, 4.44, ABq, J=15.0 Hz, 1H, 4.52, ABq, J=15.0Hz, 1H, 7.06, dist t, 2H, 7.25, m, 7H, 7.34, m, 2H, 7.46, d, J=9.5 Hz,2H, 7.90, d, J=9.0 Hz, 2H, 7.99, d, J=8.8 Hz, 1H, 8.02, d, J=8.7 Hz, 1H.MS (ES +ve) m/z 901.0 (5%) [M+H]⁺; 451.1 (100) [M+2H]²⁺.

Synthesis of Compound 15

To a stirring suspension of NaH (60% dispersion, 73 mg, 1.86 mmol) indry THF (10 ml) was added dropwise (L)-leucinol (0.2 ml, 1.55 mmol). Thesolution was then heated at reflux overnight before being cooled andwater (1 ml) added. After evaporation to near dryness the residue wastaken up in DCM (20 ml) and extracted with 1M HCl (3×20 ml). Thecombined acid extracts were then basified with 2M KOH and back extractedwith DCM (5×15 ml). The combined organic extracts were then dried(MgSO₄), filtered and evaporated to dryness to yield the desired product15(i) as a white solid (172 mg, 54%) of sufficient purity to use in thenext step.

¹H NMR (300 MHz, CDCl₃) δ 0.87, d, J=5.4 Hz, 3H, 0.89, d, J=5.4 Hz, 3H,1.23, m, 1H, 1.41, m, 1H, 1.56, m, 1H, 2.42, br s, NH₂; 2.74, m, 1H,3.31, dABq, J=10.7 Hz, J₂=6.2 Hz, 1H, 3.55, dABq, J=10.7 Hz, J₂=3.9 Hz,1H, 3.76, ABq, J=12.9, Hz, 1H, 3.82, ABq, J=12.9, Hz, 1H, 7.32, m, SH.MS (ES +ve) m/z 208 (100%) [M+H]⁺,

This compound was prepared in two steps. The initial coupling reactionvia Protocol 1, using 15(i) (140 mg, 0.675 mmol) andFmoc-(D)-arg(Pbf)-OH (438 mg, 0.675 mmol) to yield the Fmoc protectedprecursor 15(ii) as an off white foamy solid (MS (ES +ve) m/z 837.9 (25%[M+H]⁺; 419.8 (100) [M+2H]²⁺). This compound was then deprotected viaProtocol 2, 15(ii) (200 mg, 0.238 mmol) to afford a colourless oil15(iii) (27 mg, 18% two steps).

¹H NMR (300 MHz, CDCl₃) δ 0.88, d, J=6.5 Hz, 3H, 0.89, d, J=6.5 Hz, 3H,1.25, m, 2H, 1.44, s, 6H, 1.56, m, 3H, 1.70, m, 2H, 2.02, br s, NH₂;2.08, s, 3H, 2.50, s, 3H, 2.57, s, 3H, 2.93, s, 2H, 3.15, m, 2H, 3.40,m, 2H, 3.63, m, 1H, 4.13, m, 1H, 4.45, ABq, J=12.1 Hz, 1H, 4.50, ABq,J=12.1 Hz, 1H, 6.34, br s, NH; 7.29, m, 5H, 7.39, d, J=9.0 Hz, NH. MS(ES +ve) m/z 616.3 (100%) [M+H]⁺.

This compound was prepared via Protocol 1, using 6(vi) (58 mg, 0.090mmol) and 15(iii) (53 mg, 0.086 mmol) to yield 15(iv) as a white solid(53 mg, 50%).

¹H NMR (500 MHz, CDCl₃) δ 0.49, d, J=6.5 Hz, 3H, 0.53, d, J=6.6 Hz, 3H,0.79, m, 2H, 0.88, d, J=6.6 Hz, 3H, 0.90, d, J=6.7 Hz, 3H, 0.95, m, 2H,1.21, m, 6H, 1.42, s, 6H, 1.44, s, 9H, 1.56, m, 5H, 1.83, m, 1H, 2.07,s, 3H, 2.49, s, 3H, 2.56, s, 3H, 2.91, s, 2H, 2.93, m, 2H, 3.17, m, 2H,3.41, dABq, J=9.6 Hz, J₂=5.2 Hz, 1H, 3.45, dABq, J₁=9.6 Hz, J₂=4.6 Hz,1H, 3.89, m, 1H, 4.01, m, 2H, 4.17, m, 1H, 4.46, m, 5H, 4.76, m, NH;6.13, d, J=6.8 Hz, NH; 6.17, br s, NH; 6.66, d, J=8.4 Hz, NH; 7.14, m,2H, 7.24, m, 4H, 7.30, m, 6H, 7.42, d, J=9.0 Hz, 1H; 7.84, d, J=8.4 Hz,1H, 7.86, d, J=8.4 Hz, 1H, 7.92, d, J=8.8 Hz, 1H, 7.93, d, J=8.8 Hz, 1H.MS (ES +ve) m/z 1240 (100%) [M+H]⁺; 832.4 (100) [M+H-BOC-pbf-ibu]⁺.

This compound was prepared via Protocol 3, using 15(iv) (50 mg, 0.040mmol) to yield 15 as a white solid (32 mg, 83%).

¹H NMR (500 MHz, CDCl₃) δ 0.51, d, J=6.6 Hz, 3H, 0.56, d, J=6.6 Hz, 3H,0.90, d, J=6.7 Hz, 3H, 0.92, m, 2H, 0.93, d, J=6.7 Hz, 3H, 1.24, m, 4H,1.64, m, 9H, 1.84, m, 1H, 2.75, m, 2H, 3.17, m, 2H, 3.43, d, J=7.4 Hz,2H, 3.92, m, 1H, 4.12, m, 2H, 4.29, m, 1H, 4.49, m, 4H, 7.06, dist t,2H, 7.21, m, 2H, 7.34, m, 7H, 7.47, d, J=9.1 Hz, 1H, 7.54, d, J=9.1 Hz,1H, 7.91, d, J=8.8 Hz, 1H, 7.92, d, J=8.8 Hz, 1H, 8.02, d, J=9.3 Hz, 2H.MS (ES +ve) m/z 888.3 (10%) [M+H]⁺; 444.9 (100) [M+2H]²⁺.

Synthesis of Compound 16 & Compound 17

To a suspension of L-leucine (1.17 g, 8.92 mmol) and phthalic anhydride(1.26 g, 8.51 mmol) in toluene (25 ml) was added triethylamine (0.11 ml,0.79 mmol). The flask was fitted with a Dean-Stark water separator and acondenser and heated at vigorous reflux for 3 hours. The cooled solutionwas concentrated in vacuo, suspended in 2.5% HCl (50 ml) and extractedwith ethyl acetate (3×25 ml). The combined organic layers were extractedwith sat. aqueous sodium bicarbonate (3×25 ml), acidified with 10% HCland back-extracted with ethyl acetate (3×25 ml). The organic layers weredried (MgSO₄) and concentrated in vacuo to give the product 16(i) as awhite solid (2.12 g, 95%).

¹H NMR (500 MHz, CDCl₃) δ 0.87, dd, J=10.7, 6.6 Hz, 6H, 1.44, m, 1H,1.89, m, 1H, 2.30, m, 1H, 4.93, dd. J=11.3, 4.4 Hz, 1H, 7.67, dd, J=5.3,2.8 Hz, 2H, 7.79, dd, J=5.3, 2.8 Hz, 2H, 11.23, br s, 1H. MS (ES −ve)m/z 260 (100%) [M−H]⁺; 216 (46) [M-COOH]⁺.

To a solution of 16(i) (0.70, 2.69 mmol) in THF (15 ml) under a N₂atmosphere at 0° C. was added dicyclohexylcarboddimide (0.76 g, 3.69mmol). The resultant solution was stirred at 0° C. for 1 hour. To thiswas added 2-amino-1-phenylethanol (0.45 g, 3.28 mmol) and the solutionwas stirred at 0° C. for 30 minutes then at room temperature (−15° C.)for a further 16 hours. The reaction mixture was filtered to remove thebyproduct DCU, then concentrated in vacuo. The crude residue wassubjected to flash silica column chromatography and elution with 50%ethyl acetate:petroleum spirit gave the title compound 16(ii) as a paleyellow oil (783 mg, 76%).

¹H NMR (500 MHz, CDCl₃) δ 0.90, d, J=6.8 Hz, 6H, 1.43, m, 1H, 1.83, m,1H, 2.30, m, 1H, 3.28, m, 1H, 3.66, m, 1H, 4.82, m, 1H, 4.87, m, 1H,6.73, br s, 1H, 7.26, m, 5H, 7.73, m, 2H, 7.83, m, 2H. MS (ES +ve) m/z381.0 (100%) [M+H]⁺; 363.0 (39); 225 (45).

To a solution of chromium trioxide (0.45 g, 4.5 mmol) in water (10 ml)was slowly added concentrated H₂SO₄ (10 ml, 95%). The cooled solutionwas then added portionwise to a solution of 16(ii) (0.72 g, 1.9 mmol) inacetone (7.5 ml) (CAUTION: exothermic reaction). The resulting solutionwas stirred at room temperature for 16 hours. The reaction mixture wasrendered basic by addition of sat. aqueous sodium carbonate and thealkaline solution was extracted with DCM (3×25 ml), brine was added tofacilitate complete separation. The organic layers were combined, dried(MgSO₄) and concentrated in vacuo. The crude residue was subjected toflash silica column chromatography, eluting with 20% ethylacetate:petroleum spirit to yield the title compound 16(iii) as a paleyellow oil (231 mg, 34%).

¹H NMR (500 MHz, CDCl₃) δ 1.02, dd, J=18.0, 6.6 Hz, 6H, 1.66, m, 1H,2.25, m, 1H, 2.60, m, 1H, 5.64, dd, J=10.9, 5.0 Hz, 1H, 7.27, m, 1H,7.28, t, J=7.8 Hz, 1H, 7.36, t, J=7.9 Hz, 2H, 7.56, d, J=7.4 Hz, 2H,7.74, dd, J=5.3, 2.9 Hz, 2H, 7.87, dd, J=5.3, 2.9 Hz, 2H. MS (ES +ve)m/z 361.0 (100%) [M+H]⁺.

To a solution of 16(iii) (0.19 g, 0.53 mmol) in ethanol (10 ml) wasadded ethylenediamine (0.14 ml, 2.25 mmol) and the resulting solutionwas heated at reflux for 5 hours. The cooled reaction mixture wasdiluted with ethyl acetate (50 ml) then extracted with 1M HCl (3×25 ml).The combined aqueous extracts were rendered alkaline with addition of 1M NaOH then extracted with DCM (3×25 ml). The combined organic extractswere dried (MgSO₄) and concentrated in vacuo to give the product 16(iv)as pale yellow crystals (100 mg, 82%).

¹H NMR (500 MHz, CDCl₃) δ 0.96, dd, J=6.2, 9.0 Hz, 6H, 1.73, m, 5H,4.13, t, J=7.2 Hz, 1H, 7.24, s, 1H, 7.31, t, J=7.7, Hz, 1H, 7.42, t,J=7.8 Hz, 2H, 7.62, d, J=7.8 Hz, 2H. MS (ES +ve) m/z 231 (100%) [M+H]⁺.

This compound was prepared via Protocol 1, using 16(iv) (0.10 g, 0.43mmol) and (R)-Fmoc-arginine(PMC)—OH (0.28 g, 0.42 mmol) in anhydrousacetonitrile (5 ml) with EDCI (0.11 g, 0.57 mmol) and HObt (0.07 g, 0.52mmol). Purification with 2% methanol:DCM gave the product 16(v) as athick off-white oil (292 mg, 79%).

¹H NMR (500 MHz, CDCl₃) δ 0.88, m, 6H, 1.23, d, J=3.2 Hz, 6H, 1.66, m,6H, 1.77, m, 2H, 2.03, m, 4H, 2.53, m, 8H, 3.23, m, 2H, 4.02, br s, 1H,4.23, m, 4H, 5.24, m, 2H, 6.37, m, 4H, 7.10, s, 1H, 7.26, m, 6H, 7.69,m, 3H, 7.67, m, 2H. MS (ES +ve) m/z 874.9 (48%) [M+H]⁺; 438 (74); 143(100).

This compound was prepared via Protocol 2, using 16(v) (0.26 g, 0.30mmol) and piperidine (0.1 ml, 1.01 mmol) in anhydrous acetonitrile (8ml). Purification with 2-10% methanol:DCM gave the product 16(vi) as apale yellow solid (189 mg, 98%).

¹H NMR (500 MHz, CDCl₃) 6; 0.94, dd, J=12.3, 6.6 Hz, 6H, 1.28, s, 6H,1.61, m, 4H, 1.79, m, 5H, 2.07, s, 3H, 2.13, br s, 2H, 2.52, s, 3H,2.54, s, 3H, 2.58, m, 2H, 3.17, m, 2H, 3.48, m, 1H, 5.23, ABquart, J=6.6Hz, 1H, 6.42, br s, 3H, 7.18, s, 1H, 7.27, m, 1H, 7.35, t, J=7.6 Hz, 2H,7.55, d, J=7.3 Hz, 2H, 8.08, br d, 1H. MS (ES +ve) m/z; 653 (100%)[M+H]⁺; 327 (41) [M+H]²⁺.

This compound was prepared via Protocol 1, 16(vi) (0.19 g, 0.29 mmol)and 6(vi) (0.19 g, 0.29 mmol) in anhydrous acetonitrile (7 ml) with EDCI(0.08 g, 0.42 mmol) and HObt (0.06 g, 0.41 mmol). Purification with 2%methanol:DCM gave product 16(vii) as an off-white solid (343 mg, 92%).

¹H NMR (300 MHz, CDCl₃) δ 0.48, dd, J=16.1, 6.4 Hz, 6H, 0.88, m, 2H,0.95, m, 7H, 1.17, m, 6H, 1.27, m, 7H, 1.41, s, 9H, 1.74, m, 8H, 2.06,s, 3H, 2.52, m, 8H, 2.81, m, 3H, 3.18, m, 1H, 3.85, m, 1H, 4.03, m, 2H,4.41, m, 3H, 4.79, m, 1H, 5.25, m, 1H, 6.15, m, 1H, 6.29, br s, 2H,7.32, m, 17H, 7.90, m, 4H. MS (ES +ve) m/z 1278 (47%) [M+H]⁺; 1277 (56)[M]⁺; 639 (100) [M+H]⁺.

Compound 16 & Compound 17

These compounds were prepared via Protocol 3, 16(vii) (0.34 g, 0.27mmol) and TFA (2 ml, 27.0 mmol) in DCM (2 ml). Precipitation frommethanol using ether (3 times) gave a mixture of two compounds that wereseparated by preparative reverse-phase HPLC to give 16 as a white solid(73 mg, 25%) and 17 as an off-white solid (62 mg, 21%).

¹H NMR (300 MHz, CD₃OD) δ 0.50, dd, J=16.9, 6.6 Hz, 6H, 0.98, m, 9H,1.21, m, 5H, 1.38, m, 4H, 1.69, m, 4H, 1.88, m, 2H, 2.73, m, 2H, 3.19,m, 1H, 3.96, m, 1H, 4.10, m, 2H, 4.45, ABquart, J=14.6 Hz, 2H, 5.22, m,1H, 7.05, t, J=6.6 Hz, 2H, 7.21, m, 2H, 7.43, m, 8H, 7.71, m, 2H, 8.00,m, 4H. MS (ES +ve) m/z 911 (16%) [M+H]⁺; 456 (100) [M+H]²⁺.

¹H NMR (300 MHz, CD₃OD) δ 0.50, dd, J=12.4, 12.4 Hz, 6H, 0.96, m, 6H,1.24, m, 20H, 2.10, m, 2H, 3.15, m, 1H, 3.98, m, 1H, 4.15, m, 2H, 4.46,m, 2H, 5.06, m, 1H, 7.09, m, 3H, 7.40, m, 4H, 7.66, m, 4H, 7.92, m, 4H,8.33, m, 2H. MS (ES +ve) m/z 992 (38%) [M+H]⁺; 496 (100) [M+H]²⁺.

Synthesis of Compound 18

A suspension of (2,3-epoxypropyl)benzene (0.5 ml, 3.80 mmol) inconcentrated ammonia solution (10 ml, 28%) was placed in a Teflon tubewith a 100 bar pressure cap, then heated in a microwave reactor at 110°C. for 30 minutes. After cooling the mixture was extracted with DCM(3×15 ml), the organic layers combined, dried (MgSO₄) and concentratedin vacuo to give the product 18(i) as colourless prisms (490 mg, 86%).

¹H NMR (300 MHz, CDCl₃) δ 2.01, br s, 3H, 2.59, m, 1H, 2.73, d, J=6.4Hz, 2H, 2.78, m, 1H, 3.72, m, 1H, 7.22, m, 5H. MS (ES +ve) m/z 152(100%) [M+H]⁺; 134 (21); 117 (12).

This compound was prepared via Protocol 1, using 18(i) (0.84, 3.23 mmol)and 16(i) in acetonitrile (10 ml), with EDCI (0.75 g, 3.94 mmol) andHObt (0.53 g, 3.97 mmol). Purification with 50% ethyl acetate:petroleumspirit gave the product 18(ii) as a colourless oil (1.02 g, 80%).

¹H NMR (300 MHz, CDCl₃) δ 0.88, dd, J=6.4, 2.1 Hz, 6H, 1.43, m, 1H,1.81, m, 1H, 2.30, m, 1H, 2.67, m, 2H, 3.01, br s, 1H, 3.07, m, 1H,3.44, m, 1H, 3.86, m, 1H, 4.84, dd, J=11.4, 4.7 Hz, 1H; 6.74, br s, 1H,7.20, m, 5H, 7.69, m, 2H, 7.80, m, 2H. MS (ES +ve) 1n1z 433 (20%)[M+K]⁺; 417 (51) [M+Na]⁺; 395 (100) [M+H]⁺.

To a solution of chromium trioxide (0.51 g, 5.1 mmol) in water (10 ml)was slowly added concentrated H₂SO₄ (10 ml, 95%). The cooled solutionwas then added portionwise to a solution of 18(ii) (0.82 g, 2.1 mmol) inacetone (7.5 ml) (CAUTION: exothermic reaction). The resulting solutionwas stirred at room temperature for 16 hours. The reaction mixture wasrendered basic by addition of sat. aqueous sodium carbonate and thealkaline solution was extracted with DCM (3×25 ml), brine was added tofacilitate complete separation. The organic layers were combined, dried(MgSO₄) and concentrated in vacuo. The crude residue was subjected toflash silica column chromatography, elution with 25% ethylacetate:petroleum spirit gave the product 18(iii) as a dark yellow oil(200 mg, 25%).

¹H NMR (300 MHz, CDCl₃) δ 0.98, dd, J=9.1, 6.4 Hz, 6H, 1.60, m, 1H,2.14, m, 1H, 2.51, m, 1H, 3.92, s, 2H, 5.52, dd, J=5.0, 11.1 Hz, 1H,6.65, s, 1H, 7.22, m, 5H, 7.72, dd, J=5.3, 3.2 Hz, 2H, 7.85, dd, J=5.6,2.9 Hz, 2H. MS (ES +ve) m/z 375 (100%) [M+H]⁺.

A solution of 18(iii) (0.20 g, 0.53 mmol) and ethylenediamine (0.20 ml,mmol) in ethanol (10 ml) was placed in a Teflon tube with a 100 barpressure cap, then heated in a microwave reactor at 100° C. for 20minutes The cooled reaction mixture was diluted with ethyl acetate (50ml) then extracted with 5% HCl (4×25 ml). The combined aqueous extractswere rendered alkaline with addition of 1 M NaOH then extracted with DCM(4×25 ml). The organic extracts were dried (MgSO₄) and concentrated invacuo to give the product 18(iv) as a thick colourless oil (111 mg,81%).

¹H NMR (300 MHz, CDCl₃) δ 0.89, m, 6H, 1.64, m, 5H, 3.95, s, 2H, 4.0, m,1H, 6.62, s, 1H, 7.26, m, 5H. MS (ES +ve) m/z 245 (83%) [M+H]⁺; 228(100) [M-NH₂]⁺.

This compound was prepared via Protocol 1, using 18(iv) (88 mg, 36 μmol)and (R)-Fmoc-arginine(PMC)—OH (240 mg, 37 μmol) in anhydrousacetonitrile (6 ml) with EDCI (95 mg, 50 μmol) and HObt (64 mg, 47μmol). Purification with 2% methanol:DCM gave the product 18(v) as apale yellow oil (302 mg, 94%).

¹H NMR (300 MHz, CDCl₃) δ 0.82, d, J=6.4 Hz, 6H, 1.24, s, 6H, 1.72, m,9H, 2.01, s, 3H, 2.54, m, 8H, 3.23, m, 2H, 3.81, s, 2H, 4.03, m, 1H,4.24, m, 3H, 5.14, q, J=7.3 Hz, 1H, 6.47, m, 5H, 7.21, m, 8H, 7.37, m,2H, 7.49, d, J=7.3 Hz, 2H, 7.69, J=7.3 Hz, 2H. MS (ES +ve) m/z 888.9,(78%) [M+H]⁺; 445.3 (100) [M+H]²⁺.

This compound was prepared via Protocol 2, using 18(v) (0.30 g, 0.34mmol) and piperidine (0.15 ml, 1.51 mmol) in anhydrous acetonitrile (7ml). Purification with 2-10% methanol:DCM gave the product 18(vi) as athick pale yellow oil (222 mg, 97%).

¹H NMR (300 MHz, CDCl₃) δ 0.88, dd, J=6.4, 5.3 Hz, 6H, 1.28, s, 6H,1.62, m, 9H, 2.08, s, 3H, 2.19, m, 2H, 2.53, s, 3H, 2.55, s, 3H, 2.57,m, 2H, 3.14, m, 2H, 3.42, m, 1H, 3.90, s, 2H, 5.09, q, J=7.0 Hz, 1H,6.38, m, 3H, 6.59, s, 1H, 7.23, m, 5H, 8.00, br d, J=8.5 Hz, 1H.

This compound was prepared via Protocol 1, using 18(vi) (0.11 g, 0.16mmol) and 6(vi) (0.10 g, 0.16 mmol) in anhydrous acetonitrile (5 ml)with EDCI (0.04 g, 0.21 mmol) and HObt (0.03 g, 0.24 mmol). Purificationwith 2-5% methanol:DCM gave the product 18(vii) as an off-white solid(131 mg, 64%).

¹H NMR (300 MHz, CDCl₃) δ 0.46, dd, J=18.25, 6.4 Hz, 6H, 0.78, m, 2H,0.89, m, 8H, 1.18, m, 14H, 1.42, s, 9H, 1.64, m, 8H, 2.08, s, 3H, 2.58,m, 10H, 2.79, br s, 1H, 2.91, m, 2H, 3.19, m, 1H, 3.92, m, 5H, 4.43, m,3H, 4.79, m, 1H, 5.10, m, 1H, 6.25, m, 3H, 7.27, m, 12H, 7.91, m, 5H. MS(ES +ve) m/z 1291 (28%) [M+H]⁺; 646 (67) [M+H]²⁺; 83 (100). HRMS (ES+ve) for C₇₃H₉₅N₈O₁₁S, calculated 1291.6841, found 1291.6835.

This compound was prepared via Protocol 3, using 18(vii) (132 mg, 0.10mmol) and TFA:TIPS:H₂O (95:2.5:2.5) (2 ml). Precipitation from methanolusing ether (3 times) gave the product 18 as an off-white powder (57 mg,62%).

¹H NMR (300 MHz, CD₃OD) δ 0.52, dd, J=16.1, 6.4 Hz, 6H, 0.91, m, 8H,1.19, m, 5H, 1.57, m, 10H, 2.78, m, 2H, 3.17, m, 2H, 3.30, m, 2H, 3.49,q, J=7.0 Hz, 2H, 4.04, m, 4H, 4.53, ABquart, J=14.1 Hz, 1H, 5.17, m, 1H,7.08, m, 2H, 7.25, m, 9H, 7.49, dd, J=17.3, 9.0 Hz, 2H, 7.89, m, 2H,8.01, dd, J=9.1, 2.6 Hz, 2H. MS (ES +ve) m/z 925 (4%) [M+H]⁺; 463.5(100) [M+H]²⁺.

Synthesis of Compound 19

To Boc-(L)-Phe-OH (265 mg, 1.00 mmol) and potassium carbonate (691 mg,5.0 mmol) in acetone (30 ml) was added benzyl bromide (0.24 ml, 2.0mmol). The resulting solution was heated at reflux overnight beforebeing cooled, filtered and evaporated to dryness. The resultant residuewas subjected to flash column chromatography over silica, eluting with5% ethyl acetate/hexane to first remove benzyl bromide, then with DCM toyield the product 19(i) as a white solid (351 mg, 99%).

¹H NMR (500 MHz, CDCl₃) δ 1.46, s, 9H, 3.12, m, 2H, 4.68, m, 1H, 5.15,ABq, J=12.3 Hz, 1H, 5.16, m, NH; 5.19, ABq, J=12.3 Hz, 1H, 7.09, m, 2H,7.25, m, 3H, 7.32, m, 2H, 7.36, m, 2H. MS (ES +ve) m/z 401.1 (40%)[M+HCOOH]⁺; 378.1 (20) [M+Na]⁺; 356.1 (25) [M+H]⁺; 300.0 (60)[M+H-C₄H₈]⁺; 256.0 (100) [M+H-BOC]⁺.

To 19(i) (346 mg, 0.973 mmol) in DCM (2 ml) was added TFA (2 ml) and theresulting solution stirred at room temperature for 3 hrs. The solutionwas then diluted with DCM (5 ml) and washed with sat. sodium bicarbonatesolution until the washings were basic. The organic layer was then dried(MgSO₄), filtered and evaporated to dryness to yield the desired product19(ii) as a colourless oil (203 mg, 82%).

¹H NMR (500 MHz, CDCl₃) δ 1.54, s, NH₂; 2.78, dABq, J=13.5 Hz, J₂=5.5Hz, 1H, 2.96, dABq, J=13.5 Hz, J₂=7.5 Hz, 1H, 3.65, m, 1H, 5.00, ABq,J=12.3 Hz, 1H, 1.56, m, NH; 5.03, ABq, J=12.3 Hz, 1H, 7.02, d, J=6.9 Hz,2H, 7.15, m, 8H. MS (ES +ve) m/z 256.1 (100%) [M+H]⁺.

This compound was prepared in two steps. The first step via Protocol 1,using 19(ii) (200 mg, 0.78 mmol) and Fmoc-(D)-arg(Pmc)-OH (464 mg, 0.70mmol) to yield the Fmoc protected precursor 19(iii) as a white foamysolid (573 mg, MS (ES +ve) m/z 899.8 (100%) [M+H]⁺). This precursor (200mg) was then deprotected via Protocol 2 to afford the desired compound19(iv) as a white solid (148 mg, 89% two steps).

¹H NMR (500 MHz, CDCl₃) δ 1.32, s, 6H, 1.44, m, 2H/NH₂; 1.66, m, 2H,1.80, dist t, 2H, 2.12, s, 3H, 2.58, s, 3H, 2.60, s, 3H, 2.61, m, 2H,3.12, m, 4H, 3.36, m, 1H, 4.81, m, 1H, 5.07, ABq, J=12.2 Hz, 1H, 5.15,ABq, J=12.2 Hz, 1H, 6.41, m, NH; 7.09, d, J=6.6 Hz, 2H, 7.25, m, 5H,7.32, m, 3H, 7.88, d, J=6.8 Hz, NH. MS (ES +ve) m/z 677.9 (100%) [M+H]⁺.

This compound was prepared via Protocol 1, using 6(vi) (122 mg, 0.190mmol) and 19(iv) (140 mg, 0.207 mmol) to yield 19(v) as a white solid(197 mg, 71%).

¹H NMR (300 MHz, CDCl₃) δ 0.48, d, J=6.2 Hz, 3H, 0.54, d, J=6.2 Hz, 3H,0.78, m, 2H, 0.89, m, 2H, 1.20, m, 8H, 1.43, s, 9H, 1.58, m, 1H, 1.78,dist t, 2H, 2.12, s, 3H, 2.60, s, 3H, 2.61, s, 3H, 2.62, m, 2H, 2.90, m,3H, 3.06, m, 2H, 3.19, m, 1H, 3.88, m, 1H, 4.06, m, 2H, 4.37, m, 1H,4.39, ABq, J=6.6 Hz, 11H, 4.52, ABq, J=6.6 Hz, 1H, 4.86, m, 1H/NH; 5.10,ABq, J=12.3 Hz, 1H, 5.18, ABq, J=12.3 Hz, 1H; 6.19, d, J=7.3 Hz, NH;6.35, br s, NH; 7.22, m, 8H, 7.33, m, 9H, 7.45, d, J=9.1 Hz, H, 7.85, d,J=8.2 Hz, 1H, 7.88, d, J=7.9 Hz, 1H, 7.96, d, J=8.7 Hz, 2H. MS (ES +ve)m/z 1301.8 (100%) [M+H]⁺.

This compound was prepared via Protocol 3, using 19(v) (195 mg, 0.148mmol) yield 19 as an off white solid (128 mg, 85%).

¹H NMR (300 MHz, CD₃OD) δ 0.46, d, J=6.6 Hz, 3H, 0.52, d, J=6.6 Hz, 3H,0.92, m, 2H, 1.08, m, 2H, 1.20, m, 2H, 1.50, m, 5H, 2.76, m, 2H, 3.03,m, 3H, 3.15, m, 1H, 3.88, m, 1H, 4.06, m, 2H, 4.28, m, 1H, 4.46, m, 2H,4.69, m, 1H, 5.11, s, 2H, 7.13, m, 8H, 7.27, m, 8H, 7.41, d, J=9.0 Hz,1H, 7.51, d, J=9.1 Hz, 1H, 7.85, m, 2H, 7.98, dist t, 2H. MS (ES +ve)m/z 936 (10%) [M+H]⁺; 468.9 (100) [M+2H]²⁺.

Synthesis of Compound 20

To 1-amino-1-cyclopentane carboxylic acid (100 mg, 0.774 mmol) in dryacetonitrile (10 ml) was added tetramethylammonium hydroxidepentahydrate (190 mg, 1.04 mmol) and the mixture stirred at roomtemperature until the acid had dissolved. Boc anhydride (300 mg, 1.37mmol) was then added and the resultant solution stirred for four days.The solvent was then removed and the resultant residue partitionedbetween water and ether. The aqueous layer was washed with an additionalportion of ether and then acidified with solid citric acid to pH 3-4.The aqueous layer was then back-extracted with ethyl acetate (3×15 ml),before being combined, dried (MgSO₄), and evaporated to dryness to yield20(i) as a pale yellow oil (101 mg, 57%).

¹H NMR (300 MHz, CDCl₃) δ 1.44, s, 9H, 1.78, m, 4H, 1.96, m, 2H, 2.29,m, 2H, 5.06, br s, NH; 10.19, br s, COOH.

To 20(i) (120 mg, 0.523 mmol) and potassium carbonate (178 mg, 1.29mmol) in acetone (25 ml) was added benzyl bromide (0.1 ml, 0.920 mmol).The resulting solution was heated at reflux overnight before beingcooled, filtered and evaporated to dryness. The resultant residue wassubjected to flash column chromatography over silica, eluting with 5%ethyl acetate/hexane to first remove benzyl bromide, then with DCM toyield the product 20(ii) as a colourless oil that solidified to a whitesolid upon standing (173 mg, 96%).

¹H NMR (500 MHz, CDCl₃) δ 1.37, s, 9H, 1.74, m, 4H, 1.91, m, 2H, 1.20,m, 2H, 5.08, br s, NH; 5.13, s, 2H, 7.30, m, 5H. MS (ES +ve) m/z 320(50%) [M+H]⁺; 220 (100) [M+H-BOC]⁺.

To 20(ii) (170 mg, 0.532 mmol) in DCM (2 ml) was added TFA (2 ml) andthe resulting solution stirred at room temperature for 90 mins. Thesolution was then diluted with ethyl acetate (5 ml) and washed with sat.sodium bicarbonate solution until the washings were basic. The organiclayer was then dried (MgSO₄), filtered and evaporated to dryness toyield the desired product 20(iii) as a pale yellow oil (102 mg, 87%).

¹H NMR (500 MHz, CDCl₃) δ 1.58, m, 2H, 1.67, s, NH₂; 1.73, m, 2H, 1.84,m, 2H, 2.08, m, 2H, 5.12, s, 2H, 7.32, m, 5H. MS (ES +ve) m/z 219.9(100%) [M+H]⁺.

This compound was prepared in two steps. The initial coupling viaProtocol 1, using 20(iii) (100 mg, 0.456 mmol) and Fmoc-(D)-arg(Pbf)-OH(296 mg, 0.456 mmol) to yield the Fmoc protected precursor 20(iv) as awhite foamy solid (MS (ES +ve) m/z 850 (100%) [M+H]⁺). This precursorwas then deprotected via Protocol 2 to afford the desired compound 20(v)as a white solid (152 mg, 53% two steps).

¹H NMR (500 MHz, CDCl₃) δ 1.44, s, 6H, 1.46, m, 2H, 1.63, m, 2H, 1.76,4H/NH₂; 1.93, m, 2H, 2.07, s, 3H, 2.24, m, 2H, 2.50, s, 3H, 2.58, s, 3H,2.93, s, 2H, 3.20, m, 2H, 3.87, m, 1H, 5.08, s, 2H, 6.37, br s, NH;6.42, br s, NH; 7.28, m, 5H, 7.52, s, NH; 7.75, m, NH. MS (ES +ve) m/z628 (100%) [M+H]⁺.

This compound was prepared via Protocol 1, using 6(vi) (100 mg, 0.155mmol) and 20(v) (141 mg, 0.224 mmol) to yield 20(vi) as a white solid(123 mg, 63%).

¹H NMR (500 MHz, CDCl₃) δ 0.47, d, J=6.4 Hz, 3H, 0.52, d, J=6.4 Hz, 3H,0.78, m, 2H, 0.94, m, 1H, 1.23, m, 7H, 1.42, s, 9H, 1.43, s, 3H, 1.44,s, 3H, 1.70, m, 4H, 1.96, m, 2H, 2.07, s, 3H, 2.11, m, 1H, 2.25, m, 1H,2.50, s, 3H, 2.57, s, 3H, 2.91, s, 2H, 2.93, m, 2H, 3.07, m, 2H, 3.87,m, 1H, 4.00, m, 2H, 4.37, m, 2H, 4.59, m, 1H, 4.79, m, NH; 5.07, s, 2H,6.15, d, J=6.9 Hz, NH; 6.25, br s, NH; 7.11, d, J=8.5 Hz, 1H, 7.15, d,J=8.5 Hz, 1H, 7.26, m, 10H, 7.43, d, J=9.1 Hz, 1H, 7.84, d, J=8.4 Hz,1H, 7.85, d, J=8.4 Hz, 1H, 7.93, d, J=6.9 Hz, 1H, 7.94, d, J=9.0 Hz, 1H.MS (ES +ve) m/z 1252 (100%) [M+H]⁺.

This compound was prepared via Protocol 3, using 20(vi) (110 mg, 0.088mmol) to yield 20 as an off white solid (83 mg, 97%).

¹H NMR (500 MHz, CD₃OD) δ 0.51, d, J=6.5 Hz, 3H, 0.57, d, J=6.5 Hz, 3H,0.95, m, 2H, 1.14, m, 2H, 1.24, m, 2H, 1.42, m, 1H, 1.57, m, SH; 1.77,m, 4H, 1.98, m, 2H, 2.12, m, 1H, 2.30, m, 1H, 2.79, m, 2H, 3.08, m, 2H,3.95, m, 1H, 4.14, m, 2H, 4.27, m, 1H, 4.45, ABq, J=14.7 Hz, 1H, 4.55,ABq, J=14.7 Hz, 1H, 5.07, ABq, J=12.3 Hz, 1H, 5.12, ABq, J=12.3 Hz, 1H,7.06, t, J=9.3 Hz, 2H, 7.20, m, 2H, 7.34, m, 7H, 7.47, d, J=8.9 Hz, 1H,7.55, d, J=9.0 Hz, 1H, 7.89, d, J=8.3 Hz, 1H, 7.92, d, J=8.3 Hz, 1H,8.01, d, J=8.9 Hz, 1H, 8.02, d, J=8.9 Hz, 1H. MS (ES +ve) m/z 900 (5%)[M+H]⁺; 450.7 (100) [M+2H]²⁺.

Synthesis of Compound 21

To Boc-1-amino-1-cyclohexane carboxylic acid (168 mg, 0.69 mmol) andpotassium carbonate (691 mg, 5.00 mmol) in acetone (30 ml) was addedbenzyl bromide (0.17 ml, 1.40 mmol). The resulting solution was heatedat reflux overnight before being cooled, filtered and evaporated todryness. The resultant residue was subjected to flash columnchromatography over silica, eluting with 5% ethyl acetate/hexane tofirst remove benzyl bromide, then with DCM to yield the product 21(i) asa colourless oil (226 mg, 98%).

¹H NMR (500 MHz, CDCl₃) δ 1.28, m, 1H, 1.38, s, 9H, 1.42, m, 2H, 1.58,m, 3H, 1.82, m, 2H, 1.98, m, 2H, 4.86, s, NH; 5.12, s, 2H, 7.32, m, 5H.MS (ES +ve) m/z 379 (70%) [M+HCOOH]⁺; 356.1 (20) [M+Na]⁺; 334.1 (40)[M+H]⁺; 278.1 (100) [M+H-C₄H₈]⁺; 234.0 (95) [M+H-BOC]⁺.

To 21(i) (218 mg, 0.654 mmol) in DCM (2 ml) was added TFA (2 ml) and theresulting solution stirred at room temperature for 3 hrs. The solutionwas then diluted with DCM (5 ml) and washed with sat. sodium bicarbonatesolution until the washings were basic. The organic layer was then dried(MgSO₄), filtered and evaporated to dryness to yield the desired product21(ii) as a pale yellow oil (121 mg, 79%).

¹H NMR (500 MHz, CDCl₃) δ 1.39, m, 6H, 1.56, m, 2H, 1.72, s, NH₂; 1.87,m, 2H, 5.06, s, 2H, 7.26, m, 5H. MS (ES +ve) m/z 234.0 (100%) [M+H]⁺.

This compound was prepared in two steps. The first step via Protocol 1,using 21(ii) (115 mg, 0.49 mmol) and Fmoc-(D)-arg(Pmc)-OH (318 mg, 0.48mmol) to yield the Fmoc protected precursor 21(iii) as a white foamysolid (402 mg, MS (ES +ve) m/z 877.9 (100%) [M+H]⁺). This precursor21(iii) (200 mg) was then deprotected via Protocol 2 to afford thedesired compound 21(iv) as a white solid (141 mg, 87% two steps).

¹H NMR (500 MHz, CDCl₃) δ 1.30, s, 6H, 1.58, m, 10H/NH₂; 1.79, dist t,2H, 1.90, m, 2H, 2.10, s, 3H, 2.57, s, 3H, 2.58, s, 3H, 2.62, m, 2H,3.14, m, 4H, 3.44, m, 1H, 5.06, ABq, J=12.6 Hz, 1H, 5.09, ABq, J=12.6Hz, 1H, 6.41, m, NH; 7.29, m, 5H, 7.80, s, NH. MS (ES +ve) m/z 656.3(100%) [M+H]⁺.

This compound was prepared via Protocol 1, using 6(vi) (122 mg, 0.190mmol) and 21(iv) (140 mg, 0.213 mmol) to yield 21(v) as a white solid(163 mg, 67%).

¹H NMR (300 MHz, CDCl₃) δ 0.49, d, J=6.4 Hz, 3H, 0.54, d, J=6.4 Hz, 3H,0.78, m, 2H, 0.92, m, 2H, 1.20, m, 6H, 1.29, s, 6H, 1.44, s, 9H, 1.53,m, 2H, 1.77, m, 3H, 1.89, m, 1H, 2.09, s, 3H, 2.55, s, 3H, 2.57, s, 3H,2.59, m, 2H, 2.89, m, 2H, 3.09, m, 2H, 3.89, m, 1H, 4.04, m, 2H, 4.36,ABq, J=14.6 Hz, 1H, 4.42, m, 1H, 4.54, ABq, J=14.6 Hz, 1H, 4.80, m, NH;5.06, s, 2H, 6.14, br s NH; 6.36, br s, NH; 7.26, m, 12H, 7.44, d, J=9.1Hz, 1H, 7.84, d, J=8.9 Hz, 1H, 7.86, d, J=7.9 Hz, 1H, 7.92, d, J=8.8 Hz,1H, 7.95, d, J=7.6 Hz, 1H. MS (ES +ve) m/z 1280.3 (100%) [M+H]⁺.

This compound was prepared via Protocol 3, using 21(v) (106 mg, 0.083mmol) to yield 21 as an off white solid (35 mg, 43%).

¹H NMR (300 MHz, CD₃OD) δ 0.50, d, J=6.4 Hz, 3H, 0.56, d, J=6.4 Hz, 3H,0.94, m, 2H, 1.18, m, 3H, 1.57, m, 13H, 1.94, m, 5H, 2.78, m, 2H, 3.08,m, 2H, 3.93, m, 1H, 4.12, m, 2H, 4.30, m, 1H, 4.42, ABq, J=14.6 Hz, 1H,4.54, ABq, J=14.6 Hz, 1H, 5.02, ABq, J=12.3 Hz, 1H, 5.09, ABq, J=12.3Hz, 1H, 7.06, dist t, 2H, 7.20, dist t, 2H, 7.32, m, 7H, 7.44, d, J=8.8Hz, 1H, 7.53, d, J=9.1 Hz, 1H, 7.90, dist t, 2H, 8.00, d, J=9.1 Hz, 1H,8.01, d, J=9.1 Hz, 1H, 8.09, s, NH. MS (ES +ve) m/z 915.0 (10%) [M+H]⁺;457.9 (100) [M+2H]²⁺.

Synthesis of Compound 22

To a solution of 1,1′-binaphth-2,2′-diol (4.89 g, 17.1 mmol) in dryacetone (40 ml) was added anhydrous potassium carbonate (3 g) under anN₂ atmosphere. After stirring for an hour a solution of allyl bromide(1.55 ml, 17.9 mmol) in acetone (20 ml) was added dropwise over a 2 hrperiod. The mixture was then heated at reflux overnight before beingcooled and filtered. The solid residue was then washed twice more withacetone (10 ml) before the combined organic extracts were evaporated todryness to yield a honey coloured oil. Subsequent flash columnchromatography with 1:3 DCM/Hexane as the eluant affords the desiredproduct 22(i) as a yellow solid (1.905 g, 53%). R_(f)=0.06 (1:1hexane/DCM). The disubstituted product (4%) and starting material (7%)were also recovered.

¹H NMR (300 MHz, CDCl₃) δ 4.48, m, 2H, 5.00, m, 2H, 5.51, m, 1H, 7.13,dist d, J=8.3 Hz, 1H, 7.28, m, 7H, 7.83, m, 3H, 7.92, d, J=9.1 Hz, 1H.

To 22(i) (1.91 g, 5.84 mmol) in dry MeOH (50 ml) was added potassiumcarbonate (8.1 g, 58.6 mmol) and bromoacetic acid (4.05 g, 29.3 mmol).The colour of the solution changed from yellow to almost clear uponaddition of the bromoacetic acid. The solution was then heated at refluxfor three hours over which time a white ppte had fallen out of solution.The reaction mixture was then evaporated to dryness and the residuedissolved in water (50 ml). This was then washed with three 30 mlportions of ether before the aqueous layer was acidified with 3M HCl.This acidified solution was then extracted with three 30 ml portions ofDCM to yield a yellow solution. This yellow solution was then dried overMgSO₄ before being evaporated to dryness to yield the product 22(ii) asa yellow foamy solid (1.87 g, 83%).

¹H NMR (300 MHz, CDCl₃) δ 4.48, m, 2H, 4.55, ABq, J=16.7 Hz, 1H, 4.67,ABq, J=16.7 Hz, 1H, 4.95, m, 2H, 5.65, m, 1H, 7.13, app t, 2H, 7.24, m,2H, 7.34, m, 3H, 7.42, d, J=9.1 Hz, 1H, 7.87, d, J=8.2 Hz, 1H, 7.87, d,J=8.2 Hz, 1H, 7.96, d, J=8.8 Hz, 1H, 7.97, d, J=8.8 Hz, 1H. MS (ES +ve)m/z 385.0 (90%) [M+H]⁺; 402.0 (100) [M+NH₄]⁺.

This compound was prepared via Protocol 1, using 22(ii) (46 mg, 0.12mmol) and 1(viii) (110 mg, 0.12 mmol) to yield the desired product22(iii) as a white solid (124 mg, 84%). R_(f)=0.16 (5% MeOH/DCM).

¹H NMR (300 MHz, CDCl₃) δ 0.78, m, 2H, 0.87, d, J=5.6 Hz, 3H, 0.89, d,J=5.6 Hz, 3H, 0.97, m, 1H, 1.20, m, 4H, 1.27, s, 6H, 1.39, m, 2H, 1.41,s, 9H, 1.63, m, 3H, 1.75, m, 3H, 2.08, s, 3H, 2.53, s, 3H, 2.56, s, 3H,2.57, m, 2H, 2.88, m, 2H, 3.13, m, 2H, 4.09, m, 1H, 4.47, m, 6H, 4.79,m, NH; 4.86, m, 2H, 5.08, ABq, J=12.3 Hz, 1H, 5.16, ABq, J=12.3 Hz, 1H,5.63, m, 1H, 6.24, m, NH; 7.10, dist d, 1H, 7.16, dist d, 1H, 7.32, m,10H, 7.42, d, J=9.3 Hz, 1H, 7.85, dist t, 2H, 7.92, d, J=8.8 Hz, 2H. MS(ES +ve) m/z 1260 (100%) [M+Na]⁺; 1238 (80) [M+H]⁺.

This compound was prepared via Protocol 3, using 22(iii) (94 mg, 0.076mmol) to yield the desired product 22 as a white solid (62 mg, 86%).

¹H NMR (300 MHz, CD₃OD) δ 0.88, d, J=5.6 Hz, 3H, 0.93, d, J=5.6 Hz, 3H,0.97, m, 2H, 1.15, m, 1H, 1.66, m, 10H, 2.79, m, 2H, 3.14, m, 2H, 4.14,m, 1H, 4.35, m, 1H, 4.46, m, 2H, 4.56, m, 3H, 4.93, m, 2H, 5.11, ABq,J=12.3 Hz, 1H, 5.17, ABq, J=12.3 Hz, 1H, 5.71, m, 1H, 7.05, m, 2H, 7.20,dist t, 2H, 7.33, m, 7H, 7.46, d, J=9.1 Hz, 1H, 7.53, d, J=9.1 Hz, 1H,7.90, dist t, 2H, 8.01, d, J=9.1 Hz, 2H. MS (ES +ve) m/z 437 (100%)[M+2H]²⁺.

Synthesis of Compound 23

Bromomethylcyclohexane (240 μl, 1.75 mmol) was added to a mixture of1,1′-binaphth-2,2′-diol (500 mg, 1.75 mmol), potassium carbonate (1.00g, 7.27 mmol) and acetone (10 ml). The mixture was stirred at reflux for3 days, and then cooled and concentrated in vacuo. The crude product waspurified by flash chromatography with 1-10% ethyl acetate-petrol aseluent to give the product 23(i) as a viscous oil (400 mg, 60%).

¹H NMR (500 MHz, CDCl₃) δ 1.51, m, 10H; 2.44, m, 1H, 3.92, m, 2H, 7.06,d, J=8.5 Hz, 1H, 7.26, m, 8H, 7.44, d, J=9.2 Hz, 1H, 7.84, d, J=8.1 Hz,1H, 7.89, dd, J=6.2, 6.2 Hz, 2H, 8.02, d, J=9.2 Hz, 1H.

To 23(i) (400 mg, 1.05 mmol) in methanol (10 ml) was added potassiumcarbonate (1.50 g, 10.9 mmol) and bromoacetic acid (900 mg, 6.48 mmol)and the mixture stirred at reflux for 2 days. The reaction mixture wascooled down, methanol removed in vacuo, and the crude residueredissolved in water and acidified with 1M HCl. Extraction with ether,drying (Na₂SO₄) and concentration gave the crude product that waspurified by flash chromatography. Elution with chloroform gave unreacted23(i) (25%). Further elution with 2% methanol-chloroform gave 23(ii) asa viscous oil (240 mg, 51.9%).

¹H NMR (500 MHz, CDCl₃) δ 0.51, m, 2H, 0.83, m, 3H, 1.17, br t, 2H,1.36, m, 4H, 3.71, m, 1H, 3.79, m; 4.49, ABq, J=16.6, 1H, 4.61, ABq,J=16.6 Hz, 1H, 7.18, m, 4H, 7.30, m, 3H, 7.40, d, J=9.3 Hz, 1H, 7.82, d,J=7.8 Hz, 1H, 7.83, d, J=7.8 Hz, 1H, 7.91, d, J=9.3 Hz, 1H, 7.92, d,J=9.3 Hz, 1H, 9.25, br s, 1H.

To a solution of (S)-allylglycine (225 mg, 1.96 mmol) in benzyl alcohol(5 mL) was added thionyl chloride (2 mL) and the resulting mixture wasallowed to stir for 16 h before addition of diethyl ether (30 mL) andextraction with water (3×30 mL). The aqueous layer was concentrated,diluted with 2M sodium bicarbonate (20 mL), and extracted with DCM (3×30mL). The combined organic fractions were dried and acidified with 1MHCl/diethyl ether (2 mL) and evaporated. The crude product dissolved ina minimal volume of MeOH and precipitated with diethyl ether to yieldthe title compound 23(iii) as a white solid (322 mg, 1.34 mmol, 68%) Mp186-191° C.

¹H NMR (300 MHz, D₂O) δ 2.55, m, 2H, 4.08, t, J=5.4 Hz, 1H, 5.11, m, 4H,5.51, m, 1H, 7.28, m, 5H. MS (CI +ve) m/z 205 (25%) [M+H]⁺.

This compound was prepared via Protocol 1, using 23(iii) (155 mg, 0.65mmol) and (R)-Fmoc-Arg(PMC)—OH (431 mg, 0.65 mmol) to afford 23(iv) (280mg, 0.33 mmol, 51%) as a white solid. Mp 78-74° C.

¹H NMR (300 MHz CDCl₃) δ 1.22, s, 6H, 1.58, m, 2H, 1.69, t, J=6.3 Hz;1.85, m, 2H, 2.05, s, 3H, 2.52, m, 4H, 2.54, s, 3H, 2.57, s, 3H, 3.20,m, 2H, 4.05, t, J=7.2 Hz, 1H, 4.24, m, 3H, 4.58, m, 1H, 4.99, m, 4H,5.61, m, 1H, 5.68, m, 1H, 6.33, m, 3H, 7.28, m, 9H, 7.51, d, J=7.5 Hz,2H, 7.69, d, J=7.5 Hz, 2H. MS (ES +ve) m/z 850 (100%) [M+H]⁺.

This compound was prepared via Protocol 2, using 23(iv) (278 mg, 0.33mmol) to yield 32(v) as a cream semi-solid (144 mg, 0.23 mmole, 70%). Mp66-68° C.

¹H NMR (300 MHz, CDCl₃) δ 1.29, s, 6H, 1.54, m, 2H, 1.68, m, 4H, 1.78,t, J=7.2 Hz, 2H, 2.09, s, 3H, 2.55, s, 3H, 2.56, s, 3H, 2.61, t, J=6.9Hz, 2H, 3.09, m, 2H, 3.16, m, 2H, 3.40, m, 1H, 4.56, m, 1H, 5.14, m, 4H,5.63, s, 1H, 6.33, m, 2H, 7.32, m, 5H, 7.60, d, J=7.8 Hz, 1H, 7.85, d,J=7.8 Hz, 1H. MS (ES +ve) m/z 628 (100%) [M+H]⁺.

This compound was prepared via Protocol 1, using 23(v) (200 mg, 0.32mmol) and (R)-Fmoc-Lys(Boc)-OH (151 mg, 0.32 mmol) to afford 23(vi) as awhite solid (202 mg, 0.19 mmol, 59%). Mp 116° C.

¹H NMR (300 MHz, CDCl₃) δ 1.41, s, 6H, 1.59, m, 2H, 1.67, m, 4H, 1.74,m, 2H, 1.95, m, 4H, 2.03, s, 3H, 2.50, m, 4H, 2.52, s, 3H, 2.55, s, 3H,3.05, m, 2H, 3.18, m, 2H, 3.98, m, 1H, 4.20, m, 2H, 4.29, m, 1H, 4.51,m, 1H, 4.59, m, 1H, 5.03, m, 4H, 5.64, m, 1H, 6.25, m, 3H, 7.29, m, 11H,7.45, m, 1H, 7.55, d, J=7.8 Hz, 2H, 7.72, d, J=7.8 Hz, 2H. MS (ES +ve)m/z 1078 (10%) [M+H]⁺; 288 (100).

This compound was prepared via Protocol 2, using 23(vi) (202 mg, 0.19mmol) to yield 23(vii) as a cream oil (157 mg, 0.18 mmole, 93%).

¹H NMR (300 MHz, CDCl₃) δ 1.31, s, 6H, 1.42, s, 9H, 1.58, m, 4H, 1.72,m, 4H, 1.80, t, J=6.3 Hz; 1.89, m, 2H, 2.10, s, 3H, 2.15, m, 2H, 2.47,m, 2H, 2.56, s, 3H, 2.58, s, 3H, 2.62, m, 2H, 3.05, m, 2H, 3.22, m, 2H,3.36, m, 1H, 4.61, m, 2H, 5.09, m, 4H, 5.63, m, 1H, 6.44, m, 3H; 7.32,m, 5H, 7.58, d, J=7.2 Hz, 1H, 8.00, d, J=7.2 Hz, 1H. MS (ES +ve) m/z 856(100%) [M+H]⁺.

This compound was prepared via Protocol 1, from acid 23(ii) with the23(vii) (80 mg, 94 μmol). Purification by radial chromatography (1-2%methanol-chloroform) gave the product 23(viii) (94 mg, 79%).

¹H NMR (500 MHz, CDCl₃) δ 0.48, m, 2H, 0.85, m, 6H, 1.28, s, 6H, 1.41,s, 9H, 1.32, m, 12H, 1.76, br t, 3H, 2.09, s, 3H, 2.55, s, 3H, 2.57, s,3H, 2.56, m, 4H, 2.91, br s, 2H, 3.09, m, 2H, 3.67, m, 1H, 3.81, m, 1H,4.12, m, 1H, 4.43, ABq, J=14.4 Hz, 1H, 4.51, ABq, J=14.4 Hz, 1H, 4.41,m, 1H, 4.60, m, 1H, 4.84, b s, 1H, 5.06, m, 2H, 5.09, ABq, 1H, J=12.5;5.18, ABq, 1H, J=12.5; 5.68, m, 1H, 6.19, br d, J=7.0 Hz, 1H, 6.26, brs, 2H, 7.25, m, 7H, 7.43, 1H, d, J=9.0 Hz; 7.85, m, 2H, 7.95, d, J=9.0Hz, 2H. MS (ES +ve) m/z 1278 (100%) [M+H]⁺.

This compound was prepared via Protocol 3, using 23(viii) (80 mg, 62.6μmol). Standard work-up gave the product 23 as a cream crystalline solid(40 mg, 65%).

¹H NMR (500 MHz, DMSO-d₆) δ 0.57, m, 2H, 0.90, m, 3H, 1.33, m, 11H,2.39, br s, 3H, 2.49, br s, 3H, 2.65, m, 2H, 2.40, m, 4H, 3.76, m, 1H,3.87, m, 1H, 4.20, m, 3H, 4.51, br s, 2H, 5.05, m, 4H, 5.70, m, 1H,6.92, d, J=8.5 Hz, 1H, 7.00, d, J=8.0 Hz, 1H, 7.27, m, 10H, 7.54, m, 1H,7.91, m, 2H, 8.02, m, 2H. MS (ES +ve) m/z 912 (45%) [M+H]⁺; 457 (100)[M+2H]²⁺.

Synthesis of Compound 24

Bromomethylcyclobutane (200 μl, 1.75 mmol) was added to a mixture of1,1′-binaphth-2,2′-diol (500 mg, 1.75 mmol), potassium carbonate (1.00g, 7.27 mmol) and acetone (10 ml). The mixture was stirred at reflux for18 h, and then cooled down and concentrated in vacuo. The crude productwas purified by flash chromatography with 1-4% ethyl acetate-petrol aseluent to give the product 24(i) as a viscous oil (300 mg, 49%).

¹H NMR (500 MHz, CDCl₃) δ 1.52, m, 6H, 2.43, m, 1H, 3.92, m, 2H, 4.95,s, 1H, 7.06, d, J=8.3 Hz, 1H, 7.28, m, 6H, 7.43, d, J=8.8 Hz, 1H, 7.84,d, J=7.8 Hz, 1H, 7.88, d, J=9.3 Hz, 1H, 7.89, d, 1H, J=8.3 Hz; 8.00, d,J=9.3 Hz, 1H.

To 24(i) (300 mg, 0.85 mmol) in methanol (10 ml) was added potassiumcarbonate (1.00 g, 7.27 mmol) and bromoacetic acid (560 mg, 4.03 mmol)and the mixture stirred at reflux for 2 days. The reaction mixture wascooled down, methanol removed in vacuo, and the crude residueredissolved in water and acidified with 1M HCl. Extraction with ether,drying (Na₂SO₄) and concentration gave the crude product that waspurified by flash chromatography. Elution with 10% methanol:DCM gave theproduct 24(ii) as a viscous oil (200 mg, 57%).

¹H NMR (500 MHz, CDCl₃) δ 1.43, m, 6H, 2.33, m, 1H, 3.80, m, 1H, 3.99,m, 1H, 4.52, ABq, 1H, J=16.5 Hz; 4.69, ABq, 1H, J=16.5 Hz; 7.15, d,J=8.5 Hz, 2H, 7.29, m, 5H, 7.43, d, J=8.8 Hz, 1H, 7.87, d, J=7.0 Hz, 2H,7.94, d, J=8.5 Hz, 1H, 7.96, d, J=8.8 Hz, 1H.

This compound was prepared via Protocol 1, using 24(ii) and 23(viii)(110 mg, 117 μmol). Purification by radial chromatography (1-3%methanol-DCM) gave the product 24(iii) (80 mg, 55%).

¹H NMR (500 MHz, CDCl₃) δ 0.79, m, 2H, 0.94, m, 1H, 1.28, s, 6H, 1.41,s, 9H, 1.38, m, 12H, 1.76, br t, 3H, 2.09, s, 3H, 2.29, m, 1H, 2.55, s,3H, 2.57, s, 3H, 2.54, m, 4H, 2.90, m, 2H, 3.08, m, 2H, 3.80, m, 1H,3.97, m, 1H, 4.09, br s, 1H, 4.41, ABq, J=14.5 Hz, 1H, 4.51, ABq, J=14.5Hz, 1H, 4.42, m, 1H, 4.59, m, 1H, 4.84, br s, 1H, 5.06, m, 2H, 5.12,ABq, J=12.5 Hz, 1H, 5.18, ABq, J=12.5 Hz, 1H, 5.66, m, 1H, 6.22, m, 3H,7.25, m, 7H, 7.43, d, J=8.8 Hz, 1H, 7.84, d, J=8.3 Hz, 1H, 7.86, d,J=8.8 Hz, 1H, 7.93, d, J=9.3 Hz, 1H, 7.94, d, J=8.8 Hz, 1H. MS (ES +ve)m/z 1250 (100%) [M+H]⁺.

This compound was prepared via Protocol 3, using 24(iii) (70 mg, 55.98μmol). Standard work-up gave the product 24 as a cream crystalline solid(35 mg, 65%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.97, br s, 1H, 1.15, br s, 1H, 1.45, m,10H, 2.10, s, 1H, 2.45, m, 5H, 2.66, br s, 1H, 3.07, br s, 3H, 3.99, m,3H, 4.34, m, 4H, 5.09, m, 4H, 5.73, br s, 1H, 6.03, m, 3H, 7.29, m, 8H,7.57, m, 2H, 8.01, m, 4H, 8.19, br s, 1H, 8.41, br s, 2H. MS (ES +ve)m/z 884 (95%) [M+H]⁺; 443 (100) [M+2H]²⁺.

Synthesis of Compound 25

1-Bromo-2-methylpropane (190 μl, 1.75 mmol) was added to a mixture of1,1′-binaphth-2,2′-diol (500 mg, 1.75 mmol), potassium carbonate (1.00g, 7.27 mmol) and acetone (10 ml). The mixture was stirred at reflux for42 h, and then cooled down and concentrated in vacuo. The crude productwas purified by flash chromatography with 1-4% ethyl acetate-petrol aseluent to give the product 25(i) as a viscous oil (280 mg, 47%). Furtherelution with 10% ethyl acetate-petrol gave unreacted diol (200 mg, 40%).

¹H NMR (300 MHz, CDCl₃) δ 0.63, d, J=6.6 Hz, 3H, 0.66, d, J=6.6 Hz, 3H,1.77, m, 1H, 3.75, m, 2H, 4.98, br s, 1H, 7.09, d, J=8.4 Hz; 7.30, m,6H, 7.44, d, J=9.3 Hz, 1H, 7.87, d, J=8.1 Hz, 1H, 7.91, d, J=8.4 Hz, 2H,8.01, d, J=9.0 Hz, 1H.

To 25(i) (280 mg, 0.82 mmol) in methanol (10 ml) was added potassiumcarbonate (500 mg, 3.63 mmol) and bromoacetic acid (454 mg, 3.27 mmol)and the mixture stirred at reflux for 4 days. The reaction mixture wascooled down, methanol removed in vacuo, and the crude residueredissolved in water and acidified with 1M HCl. Extraction with ether,drying (Na₂SO₄) and concentration gave the crude product which waspurified by flash chromatography. Elution with 4% ethyl acetate:petrolgave unreacted 25(i) (150 mg, 54%). Further elution with 10%methanol:DCM gave the product 25(ii) (100 mg, 31%).

¹H NMR (500 M, CDCl₃) δ 0.44, d, J=6.5 Hz, 3H, 0.51, d, J=7.0 Hz, 3H,1.68, m, 1H, 3.63, ABq, J=7.0, 9.5 Hz, 1H, 3.83, ABq, J=6.5, 9.5 Hz, 1H,4.56, ABq, J=17 Hz, 1H, 4.71, ABq, J=16 Hz, 1H, 7.14, d, J=8.0 Hz; 7.25,m, 2H, 7.35, m, 4H, 7.45, d, J=9.5 Hz, 1H, 7.89, d, J=8.5 Hz, 2H, 7.99,d, J=8.5 Hz, 2H.

This compound was prepared via Protocol 1, using 25(ii) with 23(viii).Purification by radial chromatography (1-4% methanol:DCM) gave theproduct 25(iii) (90 mg, 70%).

¹H NMR (500 MHz, CDCl₃) δ 0.43, d, J=7.0 Hz, 3H, 0.49, d, J=6.0 Hz, 3H,0.77, m, 2H, 0.93, m, 1H, 1.28, s, 6H, 1.41, s, 9H, 1.45, m, 7H, 1.76,br t, 3H, 2.08, b s, 2H, 2.54, s, 3H, 2.56, s, 3H, 2.56, m, 4H, 2.95, m,2H, 3.13, m, 1H, 3.60, m, 1H, 3.81, m, 1H, 4.07, br s, 1H, 4.40, ABq,J=14.5 Hz, 1H, 4.50, ABq, J=14.5 Hz, 1H, 4.40, m, 1H, 4.57, m, 1H, 4.83,b s, 1H, 5.03, m, 2H, 5.09, ABq, J=12.5 Hz; 5.18, ABq, J=12.5 Hz; 5.63,m, 1; 6.20, m, 3H, 7.26, m, 7H, 7.43, d, J=9.5 Hz, 1H, 7.85, m, 2H,7.94, d, J=9.0 Hz, 2H. MS (ES +ve) 1260 (35%) [M+Na]⁺; 1238 (15) [M+H]⁺.

This compound was prepared via Protocol 3, using 25(iii) (70 mg, 56.5μmol) to give the product 25 as a cream crystalline solid (30 mg, 56%).

¹H NMR (500 MHz, CD₃OD) δ 0.52, d, J=6.2 Hz, 3H, 0.57, d, J=6.6 Hz, 3H,0.87, m, 2H, 0.96, br s, 1H, 1.13, m, 1H, 1.62, m, 4H, 1.28, m, 2H,2.57, m, 2H, 2.79, br s, 2H, 3.15, br s, 2H, 3.70, m, 1H, 3.91, m, 1H,4.14, b s, 1H, 4.48, m, 4H, 4.89, br s, 1H, 5.11, m, 2H, 5.15, ABq, 1H,J=12.5 Hz; 5.19, ABq, 1H, J=12.5 Hz; 5.74, m, 1H, 7.09, m, 2H, 7.22, m,2H, 7.37, m, 7H, 7.47, d, J=8.5 Hz, 1H, 7.54, d, J=8.5 Hz, 1H, 7.91, d,J=7.7 Hz, 2H, 8.03, d, J=8.5 Hz, 2H. MS (ES +ve) 872 (25%) [M+H]⁺; 437(100) [M+2H]²⁺.

Synthesis of Compound 26

Bromopentane (216 μl, 1.75 mmol) was added to a mixture of1,1′-binaphth-2,2′-diol (500 mg, 1.75 mmol), potassium carbonate (1.00g, 7.27 mmol) and acetone (10 ml). The mixture was stirred at reflux for18 h, and then cooled and concentrated in vacuo. The crude product waspurified by flash chromatography with 1-4% ethyl acetate:petrol aseluent to give the product 26(i) as a viscous oil (380 mg, 61%).

¹H NMR (500 MHz, CDCl₃) δ 0.66, t, J=7 Hz, 3H, 0.96, m, 2H, 1.03, m, 2H,1.43, m, 2H, 3.95, m, 2H, 4.94, s, 1H, 7.05, d, J=8.5 Hz, 1H, 7.28, m,6H, 7.42, d, J=9.0 Hz, 1H, 7.83, d, J=8.5 Hz; 7.87, d, J=9.0 Hz, 2H,7.98, d, J=9.0 Hz, 1H.

To 26(i) (280 mg, 0.82 mmol) in methanol (10 ml) was added potassiumcarbonate (500 mg, 3.63 mmol) and bromoacetic acid (454 mg, 3.27 mmol)and the mixture stirred at reflux for 4 days. The reaction mixture wascooled down, methanol removed in vacuo, and the crude residueredissolved in water and acidified with 1M HCl. Extraction with ether,drying (Na₂SO₄) and concentration gave the crude product that waspurified by flash chromatography. Elution with 4% ethyl acetate:petrolgave unreacted 26(i) (150 mg, 54%). Further elution with 10%methanol:DCM gave the desired compound 26(ii) as a viscous oil (100 mg,31%).

¹H NMR (500 MHz, CDCl₃) δ 0.53, t, J=7.5 Hz, 3H, 0.79, m, 4H, 1.35, m,2H, 3.88, m, 1H, 4.05, m, 1H, 4.55, ABq, J=16.5 Hz, 1H, 4.74, ABq,J=16.5 Hz, 1H, 7.14, dd, J=8.5, 2.5 Hz, 1H, 7.25, dd, J=5.5, 5.5 Hz, 1H,7.33, d, J=9.5 Hz, 1H, 7.36, m, 3H, 7.46, d, J=7.46 Hz, 1H, 7.89, d,J=8.0 Hz, 1H, 7.98, d, J=8.5 Hz, 1H.

This compound was prepared via Protocol 1, using 26(ii) with 23(viii)(80 mg, 94 μmol). Purification by radial chromatography (1-4%methanol:DCM) gave the desired product 26(iii) (110 mg, 95%).

¹H NMR (500 MHz, CDCl₃) δ 0.54, d, J=7.2 Hz, 3H, 0.83, m, 7H, 1.27, s,6H, 1.41, s, 9H, 1.33, m, 8H, 1.76, br t, 3H, 2.08, br s, 3H, 2.54, s,3H, 2.56, s, 3H, 2.53, m, 4H, 2.90, m, 2H, 3.06, m, 4H, 3.85, m, 1H,4.00, m, 1H, 4.08, br s, 1H, 4.40, ABq, J=14.5 Hz, 1H, 4.52, ABq, J=14.5Hz, 1H, 4.54, m, 2H, 4.85, br s, 1H, 5.05, m, 2H, 5.15, ABq, J=12.0 Hz,1H, 5.17, ABq, J=12.0 Hz, 1H, 5.65, m, 1H, 6.23, m, 3H, 7.11, d, J=8.3Hz, 1H, 7.15, d, J=8.3 Hz, 1H, 7.26, m, 10H, 7.44, d, J=9.05 Hz; 7.85,m, 2H, 7.93, m, 2H. MS (ES +ve) m/z 1252 (100%) [M+H]⁺.

This compound was prepared via Protocol 3, using 26(iii) (90 mg, 71.9μmol). Standard work-up gave the product 26 as a white crystalline solid(45 mg, 65%).

MS (ES +ve) m/z 886 (70%) [M+H]⁺; 444 (100) [M+2H]²⁺.

Synthesis of Compound 27

1-Bromo-2,2-dimethylpropane (220 μl, 1.75 mmol) was added to a mixtureof 1,1′-binaphth-2,2′-diol (500 mg, 1.75 mmol), potassium carbonate(1.00 g, 7.27 mmol) and dimethylformamide (10 ml). The mixture wasstirred at 80° C. for 7 days, and then cooled down and acidified withdiluted hydrochloric acid. The mixture was diluted with water andextracted with ether. The crude product was purified by flashchromatography with 1-4% ethyl acetate:petrol as eluent to give theproduct 27(i) as a viscous oil (80 mg, 13%).

¹H NMR (500 MHz, CDCl₃) δ 0.57, s, 9H, 3.57, m, 2H, 4.94, s, 1H, 7.05,d, 1H, J=8.5 Hz; 7.17, m, 1H, 7.26, m, 2H, 7.35, m, 4H, 7.81, d, J=8 Hz,1H, 7.85, d, J=9 Hz, 2H, 7.95, d, J=9.5 Hz, 1H.

To 27(i) (80 mg, 0.22 mmol) in methanol (10 ml) was added potassiumcarbonate (1.00 g, 7.27 mmol) and bromoacetic acid (560 mg, 4.03 mmol)and the mixture stirred at reflux for 18 h. The reaction mixture wascooled down, methanol removed in vacuo, and the crude residueredissolved in water and acidified with 1M HCl. Extraction with ether,drying (Na₂SO₄) and concentration gave the crude product that waspurified by flash chromatography. Elution with 10% methanol:DCM gave theacid 27(ii) as a viscous oil (85 mg, 92%).

¹H NMR (500 MHz, CDCl₃) δ 0.50, s, 9H, 3.51, ABq, J=8.0 Hz, 1H, 3.66,ABq, J=8.0 Hz, 1H, 4.52, s, 2H, 7.20, m, 4H, 7.32, m, 3H, 7.38, d, J=9.0Hz, 1H, 7.85, d, J=8.5 Hz, 2H, 7.93, m, 2H.

This compound was prepared via Protocol 1, using 27(ii) and 23(viii) (82mg, 96 μmol). Purification by radial chromatography (1-3% methanol:DCM)gave the product 27(iii) (73 mg, 61%).

¹H NMR (300 MHz, CDCl₃) δ 0.47, s, 9H, 0.80, m, 2H, 0.91, m, 1H, 1.28,s, 6H, 1.41, s, 9H, 1.40, m, 6H, 1.77, br t, 3H, 2.08, s, 3H, 2.54, 4H,3.11, m, 4H, 3.48, ABq, J=8.1 Hz, 1H, 3.72, ABq, J=8.4 Hz, 1H, 4.08, brs, 1H, 4.49, m, 4H, 4.84, br s, 1H, 5.03, m, 2H, 5.09, ABq, J=12.3 Hz,1H, 5.18, ABq, J=12.3 Hz, 1H, 5.66, m, 1H, 6.13, d, J=7.2 Hz, 1H, 6.30,br s, 2H, 7.27, m, 7H, 7.42, d, J=9.0 Hz, 1H, 7.85, m, 2H, 7.94, d,J=8.7 Hz, 2H. MS (ES +ve) m/z 1252 (20%) [M+H]⁺.

This compound was prepared via Protocol 3, using 27(iii) (60 mg, 47.9μmol). Standard work-up gave the product 27 as a cream crystalline solid(30 mg, 65%).

¹H NMR (300 MHz, CD₃OD) δ 0.52, br s, 9H, 1.05, m, 3H, 1.66, m, 6H,2.52, m, 2H, 2.79, br s, 2H, 3.34, br s, 2H, 3.55, ABq, J=8.1 Hz, 1H,3.79, ABq, J=8.1 Hz, 1H, 4.14, br s, 1H, 4.42, m, 4H, 4.86, br s, 1H,5.11, m, 4H, 5.73, m, 1H, 7.31, 13H, 7.90, d, J=8.1 Hz, 2H, 8.02, d,J=8.4 Hz, 2H. MS (ES +ve) m/z 887 (20%) [M+H]⁺; 444 (100) [M+2H]²⁺.

Synthesis of Compound 28

2-Bromoethylbenzene (240 μl, 1.75 mmol) was added to a mixture of1,1′-binaphth-2,2′-diol (500 mg, 1.75 mmol), potassium carbonate (1.00g, 7.27 mmol) and acetone (10 ml). The mixture was stirred at reflux for18 h, and then cooled down and filtered. The crude product was purifiedby flash chromatography with 1-4% ethyl acetate:petrol as eluent to givethe product 28(i) as viscous oil (250 mg, 37%)

¹H NMR (300 MHz, CDCl₃) δ 2.69, m, 2H, 4.12, m, 2H, 4.90, s, 1H, 6.76,m, 2H, 7.02, m, 4H, 7.26, m, 7H, 7.89, m, 4H.

To 28(i) (250 mg, 0.64 mmol) in methanol (10 ml) was added potassiumcarbonate (1.00 g, 7.27 mmol) and bromoacetic acid (560 mg, 4.03 mmol)and the mixture stirred at reflux for 18 h. The reaction mixture wascooled down, methanol removed in vacuo, and the crude residueredissolved in water and acidified with 1M HCl. Extraction with ether,drying (Na₂SO₄) and concentration gave the crude product that waspurified by flash chromatography. Elution with 10% methanol-DCM gave theacid 28(ii) as a viscous oil (257 mg, 89%).

¹H NMR (500 MHz, CDCl₃) δ 2.62, m, 2H, 4.06, m, 2H, 4.15, m, 2H, 6.67,d, J=7.5 Hz, 2H, 6.98, m, 3H, 7.15, m, 3H, 7.27, m, 2H, 7.34, m, 3H,7.80, d, J=8.5 Hz, 1H, 7.89, m, 3H, 10.30, br s, 1H.

This compound was prepared via Protocol 1, using 28(ii) and 1(viii) (100mg, 115 μmol). Purification by radial chromatography (1-3% methanol:DCM)gave the product 28(iii) (83 mg, 56%).

¹H NMR (300 M, CDCl₃) δ 0.75, m, 2H, 0.89, m, 6H, 1.26, s, 6H, 1.40, s,9H, 1.60, m, 6H, 1.76, br t, 3H, 2.08, s, 3H, 2.62, m, 4H, 3.00, m, 4H,4.05, m, 2H, 4.31, m, 4H, 4.54, m, 1H, 4.80, m, 1H, 5.09, ABq, J=12.6Hz, 1H, 5.17, ABq, J=12.6 Hz, 1H, 6.10, br d, J=7.2 Hz, 1H, 6.31, br s,2H, 6.59, d, J=6.9 Hz, 2H, 6.99, m, 1H, 7.22, m, 9H, 7.82, d, J=8.1 Hz,1H, 7.90, m, 2H. MS (ES +ve) m/z 1302 (100%) [M]⁺.

This compound was prepared via Protocol 3, using 28(iii) (80 mg, 61.4μmol). Standard work-up gave the product 28 as a cream crystalline solid(40 mg, 65%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.47, m, 6H, 1.12, m, 3H, 1.47, m, 4H, 2.07,s, 1H, 2.41, m, 1H, 2.49, br s, 3H, 2.66, m, 1H, 2.66, m, 1H, 3.04, m,1H, 3.55, m, 8H, 4.26, m, 4H, 5.03, m, 2H, 5.74, m, 1H, 6.94, br d,J=8.4 Hz, 1H, 7.02, br d, J=8.4 Hz, 1H, 7.30, m, 15H, 7.51, m, 1H, 7.92,m, 2H, 8.02, m, 2H. MS (ES +ve) m/z 936 (100%) [M]⁺.

Synthesis of Compound 29

This compound was prepared via Protocol 1, using 23(vii) (121 mg, 0.14mmol) and 1(ii) (58 mg, 0.14 mmol) to afford 29(i) as a white solid (114mg, 65%) Mp 90-94° C.

¹H NMR (300 MHz, CDCl₃) δ 0.46, d, J=6.3 Hz, 3H, 0.52, d, J=6.3 Hz, 3H,0.79, m, 4H, 0.92, m, 2H, 1.12, m, 2H, 1.26, s, 6H, 1.41, s, 9H, 1.52,m, 4H, 1.76, t, J=5.7 Hz, 1H, 2.09, s, 3H, 2.49, m, 2H, 2.55, s, 3H,2.56, s, 3H, 2.64, m, 2H, 2.92, m, 2H, 3.14, m, 2H, 3.95, m, 2H, 4.80,m, 5H, 5.05, m, 2H, 5.13, ABq, J=12.3 Hz, 2H, 5.65, m, 1H, 6.18, d,J=6.9 Hz, 1H, 6.29, br s, 2H, 6.47, m, 1H, 7.30, m, 13H, 7.90, m, 4H. MS(ES +ve) m/z 1274 (100%) [M+NH₄]⁺.

This compound was prepared via Protocol 3, using 29(i) (114 mg, 0.091mmol) to yield 29 as a highly hydroscopic cream solid (48 mg, 55%).

¹H NMR (500 MHz, CD₃OD) δ 0.47, d, J=6.3 Hz, 3H, 0.53, d, J=6.3 Hz, 3H,0.96, m, 2H, 1.17, m, 2H, 1.24, m, 2H, 1.55, m, 4H, 1.71, m, 2H, 1.79,m, 2H, 2.55, m, 2H, 2.79, m, 2H, 3.14, m, 2H, 3.95, m, 1H, 4.14, m, 2H,4.35, m, 1H, 4.49, m, 3H, 5.11, m, 4H, 5.74, m, 1H, 5.32, m, 13H, 7.96,m, 4H. MS (ES +ve) m/z 886 (5%) [M]²⁺; 444 (100%).

To 1(i) (10.0 g, 28 mmol) in dry acetone (200 ml) was added potassiumcarbonate (20.0 g, 145 mmol), chloroacetonitrile (3.0 ml, 47 mmol) andpotassium iodide (2.50 g, 15 mmol). The resultant solution was heated atreflux for 18 hrs and then cooled down and filtered. Acetone was removedand the residue redissolved in ethyl acetate and water, and neutralizedwith 1M HCl. Organic extract was separated and water phase extractedwith more ethyl acetate. Organic extracts were combined, dried (MgSO₄)and concentrated. Purification by column chromatography with 1-20% ethylacetate/petrol gave the product 30(i) as a colourless viscous oil (10.0g, 90%).

¹H NMR (300 MHz, CDCl₃) δ 0.54, d, J=6.0 Hz, 3H, 0.60, d, J=5.7 Hz, 3H,1.25, m, 2H, 3.89, m, 1H, 4.05, m, 1H, 7.22, m, 6H, 7.38, d, J=9.0 Hz,1H, 7.40, d, J=9.3 Hz, 1H, 7.80, d, J=7.5 Hz, 7.81, d, J=8.1 Hz, 1H,7.90, d, J=9.0 Hz, 1H, 7.91, d, J=9.3 Hz, 1H.

A solution of 30(i) (10.00 g, 25 mmol) in dry ether (50 ml) was addeddropwise to a suspension of lithium aluminium hydride (3.00 g, 79 mmol)in ether (30 ml) during 2 hrs with ice bath cooling, and then stirredfor 18 hrs at room temperature. Ether (100 ml) was added to the reactionmixture and then a potassium hydroxide solution in water (20%) was addeduntil a white precipitate separated on the bottom of the flask. Ethersolution was filtered to give the crude product that was purified bycolumn chromatography to give the product 30(ii) (8.05 g, 80%).

¹H NMR (300 MHz, CDCl₃) δ 0.55, d, J=6.3 Hz, 3H, 0.60, d, J=6.3 Hz, 3H,0.87 m, 1H, 1.22, m, 4H, 2.64, br s, 2H, 3.95, m, 4H, 7.20, m, 4H, 7.31,m, 2H, 7.38, d, J=8.7 Hz, 1H, 7.41, d, J=8.7 Hz, 1H, 7.84, d, J=8.1 Hz,2H, 7.91, d, J=8.7 Hz, 2H.

This compound was prepared via Protocol 1, using 30(ii) (260 mg, 0.65mmol) and (R)-Fmoc-Lys(Boc)-OH (305 mg, 0.65 mmol) to yield the desiredproduct 30(iii) as an off white solid (310 mg, 56%).

¹H NMR (300 MHz, CDCl₃) δ 0.41, d, J=6.0 Hz, 3H, 0.53, d, J=6.5 Hz, 3H,1.27, m, 11H, 1.44, s, 9H, 2.85, m, 2H, 3.35, m, 2H, 3.81, m, 2H, 4.03,m, 2H, 4.12, m, 1H, 4.21, m, 1H, 4.38, m, 2H, 4.53, m, 1H, 5.38, br d,1H, 5.78, br s, 1H, 7.09, d, J=8.5 Hz, 1H, 7.25, m, 10H, 7.49, d, J=9.0Hz, 1H, 7.58, d, J=7.0 Hz, 2H, 7.73, d, J=7.5 Hz, 2H, 7.85, d, J=8.0 Hz,1H, 7.90, d, J=7.5 Hz, 1H, 7.94, d, J=9.0 Hz, 1H, 8.00, d, J=9.0 Hz, 1H.MS (ES +ve) m/z 849 (100%) [M+Na]⁺.

This compound was prepared via Protocol 2, using 30(iii) (310 mg, 0.365mmol) to yield the desired product 30(iv) as an off white solid (172 mg,75%).

¹H NMR (300 MHz, CDCl₃) δ 0.58, 3H, dd, J=6.3, 1.5 Hz; 0.65, 3H, dd,J=6.6, 1.5 Hz; 1.51, m, 11H, 1.51, s, 9H, 2.93, m, 1H, 3.17, m, 3H,3.30, m, 1H, 3.45, m, 1H, 3.92, m, 1H, 4.12, m, 3H, 4.79, br s, 1H,6.73, m, 1H, 7.15, m, 1H, 7.25, m, 3H, 7.36, m, 2H, 7.48, m, 2H, 7.91,m, 2H, 7.99, m, 2H. MS (ES +ve) m/z 628 (100%).

This compound was prepared via Protocol 1, using 30(iv) (172 mg, 0.274mmol) and (R)-Fmoc-Arg(Pmc)-OH (182 mg, 0.274 mmol) to yield the desiredproduct 30(v) as an off white solid (165 mg, 47%).

¹H NMR (300 MHz, CDCl₃) δ 0.41, d, J=6.6 Hz, 3H, 0.52, d, J=6.3 Hz, 3H,1.25, s, 6H, 1.37, s, 9H, 1.30, m, 13H, 1.71, br t, 3H, 1.83, br s, 1H,2.07, s, 3H, 2.55, s, 3H, 2.59, s, 3H, 2.84, m, 3H, 3.19, m, 4H, 3.81,m, 1H, 4.02, m, 3H, 4.12, m, 1H, 4.31, m, 3H, 4.84, br s, 1H, NH; 6.22,m, 5H, NH; 7.21, m, 10H, 7.48, m, 4H, 7.70, d, J=7.5 Hz, 2H, 7.89, m,4H. MS (ES +ve) m/z 1272 (5%) [M+H]⁺.

This compound was prepared via Protocol 2, using 30(v) (165 mg, 0.130mmol) to yield the desired product 30(vi) as an off white solid (100 mg,73%).

¹H NMR (300 MHz, CDCl₃) δ 0.41, d, J=6.6 Hz, 3H, 0.53, d, J=6.3 Hz, 3H,1.28, s, 6H, 1.41, s, 9H, 1.36, m, 14H, 1.77, br t, 3H, 2.10, s, 3H,2.56, s, 3H, 2.58, s, 3H, 2.92, m, 2H, 3.20, m, 3H, 3.37, m, 2H, 3.81,m, 1H, 4.08, m, 4H, 4.84, br s, 1H, NH; 6.22, m, 5H, NH; 7.23, m, 6H,7.38, d, J=9.0 Hz, 1H, 7.49, d, J=9.0 Hz, 1H, 7.96, m, 4H.

This compound was prepared via Protocol 1, using 30(vi) (100 mg, 95μmol) and (R)-Fmoc-Leu-OH (34 mg, 95 μmol) to yield the desired product30(vii) as an off white solid (120 mg, 91%).

¹H NMR (300 MHz, CDCl₃) 0.41, br d, J=6.0 Hz, 3H, 0.51, br d, J=6.3 Hz,3H, 0.88, br d, J=5.7 Hz, 3H, 0.90, br d, J=5.7 Hz, 3H, 1.24, s, 6H,1.39, s, 9H, 1.56, m, 23H, 2.06, s, 3H, 2.51, s, 3H, 2.54, s, 3H, 2.71,s, 1H, 2.88, m, 2H, 3.11, m, 3H, 3.31, m, 1H, 3.77, m, 1H, 3.98, m, 2H,4.11, m, 1H, 4.27, m, 2H, 4.54, br s, 1H, NH; 4.92, br s, 1H, NH; 6.35,m, 5H, NH; 7.26, m, 10H, 7.55, m, 4H, 7.70, d, J=7.2 Hz, 2H, 7.89, m,4H. MS (ES +ve) m/z 1385 (15%) [M]⁺.

This compound was prepared via Protocol 2, using 30(vii) (120 mg, 87μmol) to yield the desired product 30(viii) as an off white solid (80mg, 79%).

MS (ES +ve) m/z 1163 (80%) [M]⁺.

This compound was prepared via Protocol 1, using 30(viii) (50 mg, 43μmol) and phenylacetic acid (6 mg, 43 μmol) to yield the desired product30(ix) as a cream solid (50 mg, 91%).

¹H NMR (300 MHz, CDCl₃) δ 0.43, d, J=6.0 Hz, 3H, 0.53, d, J=6.3 Hz, 3H,0.80, br d, 3H, 0.83, br d, 3H, 1.28, s, 6H, 1.26, m, 14H, 1.41, s, 9H,1.77, br t, 3H, 2.09, s, 3H, 2.53, s, 3H, 2.55, s, 3H, 2.90, m, 3H,3.13, m, 2H, 3.29, m, 1H, 3.50, m, 2H, 3.62, s, 2H, 3.81, m, 1H, 3.99,m, 4H, 4.46, m, 2H, 4.86, br s, 1H, 6.25, m, 5H, 7.24, m, 11H, 7.89, m,6H. MS (ES +ve) m/z 1303 (75%) [M+Na]⁺.

This compound was prepared via Protocol 3, using 30(ix) (50 mg, 39 μmol)to yield the desired product 30 as a cream solid (20 mg, 56%).

¹H NMR (300 MHz, CDCl₃) δ 0.48, d, J=6.3 Hz, 3H, 0.57, d, J=6.6 Hz, 3H,0.88, br d, 3H, 0.95, br d, 3H, 1.19, m, 6H, 1.58, m, 7H, 2.82, br s,2H, 3.27, m, 7H, 3.65, m, 2H, 3.87, m, 1H, 4.07, m, 4H, 4.27, m, 2H,4.54, br s, 1H, NH; 4.92, br s, 1H, NH; 6.35, m, 5H, NH; 7.22, m, 10H,7.55, m, 4H, 7.70, d, J=7.2 Hz, 2H, 7.89, m, 4H. MS (ES +ve) m/z 915(5%) [M]⁺, 458 (100) [M+2H]²⁺.

Synthesis of Compound 31

To Fmoc-(D)-Arg(Pmc)-OH (400 mg, 604 mmol) suspended in DCM was addedSOCl₂ (2 ml) at 0° C. After stirring for an hour the solvent was removedand the resultant residue resuspended in DCM and BzOH (0.1 ml) added.The solution was then stirred overnight at 40° C. before beingevaporated to dryness. The crude residue was then subjected to flashcolumn chromatography over silica using 2% MeOH/DCM as the eluant toafford the desired product 31(i) as a white solid (341 mg, 75%).

¹H NMR (300 MHz, CDCl₃) δ 1.29, s, 6H, 1.51, m, 2H, 1.74, m, 4H, 2.11,s, 3H, 2.58, m, 8H, 3.13, m, 2H, 4.14, m, 1H, 4.34, m, 3H, 5.11, s, 2H,5.98, d, J=9.2 Hz, NH; 6.16, br s, NH; 6.29, br s, NH; 7.30, m, 9H,7.58, d, J=7.5 Hz, 2H, 7.75, d, J=7.2 Hz, 2H.

This compound was prepared via Protocol 2, using 31(i) (341 mg, 0.463mmol) to yield the desired product 31(ii) as a white solid (159 mg,65%).

¹H NMR (300 MHz, CDCl₃) δ 1.27, s, 6H, 1.51, m, 2H, 1.78, m, 4H, 2.07,s, 3H, 2.52, m, 8H, 3.11, m, 2H, 3.41, m, 1H, 5.07, s, 2H, 6.38, s, NH;7.30, m, 5H.

To a suspension of (S)-1,1′-binaphth-2,2′-diol (1 g, 3.5 mmol) andanhydrous potassium carbonate (2.4 g, 5 equiv) dissolved in acetone (25ml), was added ethyl bromobutyrate (1.15 ml, 2.3 equivalents) under anN₂ atmosphere. The mixture was then heated at reflux for 24 hrs beforebeing evaporated to dryness and the residue partitioned between ethylacetate and water. The organic layer was then washed twice with waterbefore being dried and evaporated to dryness to yield an oil 31(iii)which was used in the next step without further purification.

¹H NMR (300 MHz, CDCl₃) δ 1.17, t, J=7.2 Hz, 6H, 1.70, m, 4H, 1.85, m,4H, 3.98, m, 8H, 7.17, m, 4H, 7.30, m, 2H, 7.39, d, J=8.8 Hz, 2H, 7.84,d, J=8.0 Hz, 2H, 7.92, d, J=8.8 Hz, 2H. MS (EI) m/z 514 (90%) [M]⁺; 400(80); 115 (100).

To 31(iii) (598 mg, 1.52 mmol) dissolved in THF (30 ml), was added asolution of LiOH (250 mg, 10.5 mmol) in water (20 ml), After stirring atRT for 4 hrs, diethyl ether was added and the layers separated. Theaqueous layer was then acidified with 1M HCl before being extracted withdiethyl ether (3×20 ml). The combined organic extracts were then dried(MgSO₄) and evaporated to dryness to yield the product 31(iv) as a whitefoamy solid (342 mg, 64%).

¹H NMR (300 MHz, CDCl₃) δ 1.65, m, 4H, 1.82, m, 4H, 3.93, m, 2H, 3.98,m, 2H, 7.15, m, 4H, 7.27, m, 2H, 7.35, d, J=9.1 Hz, 2H, 7.81, d, J=8.2Hz, 2H, 7.90, d, J=8.8 Hz, 2H, 11.84, br s, 1H. MS (EI) m/z 458 (50%)[M]⁺; 372 (25) [M-CH₂CH₂CH₂COOH]⁺; 286 (100) [M-2×CH₂CH₂CH₂COOH]⁺.

This compound was prepared via protocol 1, using 31(ii)(159 mg, 0.30mmol) and 31(iv)(68.7 mg, 0.15 mmol) to yield 31(v) as a white solid(124 mg, 59%).

¹H NMR (300 MHz, CDCl₃) δ 1.25, s, 12H, 1.34, m, 8H, 1.70, m, 12H, 2.06,s, 6H, 2.51, m, 16H, 3.05, m, 4H, 3.75, m, 2H, 3.96, m, 2H, 4.34, m, 2H,5.04, s, 4H, 6.11, br s, NH; 6.22, br s, NH; 6.42, d, J=7.2 Hz; NH;7.06, d, J=8.5 Hz, 2H, 7.15, dist t, 2H, 7.25, m, 12H, 7.32, d, J=9.1Hz; 2H, 7.79, d, J=8.2 Hz, 2H, 7.85, d, J=8.0 Hz, 2H. MS (ES +ve) m/z742.7 (100%) [M+H]²⁺.

This compound was prepared via Protocol 3, using 31(v) (124 mg, 0.089mmol) to yield 31 as a white solid (65.9 mg, 73%).

¹H NMR (300 MHz, CD₃OD) δ 1.58, m, 4H, 1.70, m, 6H, 1.85, m, 2H, 1.95,m, 4H, 3.12, m, 4H, 3.98, m, 4H, 4.38, m, 2H, 5.08, s, 4H, 7.06, m, 2H,7.15, m, 2H, 7.25, m, 12H, 7.42, m, 2H, 7.83, m, 2H, 7.95, m, 2H. MS (ES+ve) m/z 951.2 (10%) [M+H]⁺; 476.8 (100) [M+H]²⁺.

Synthesis of Compound 32

This compound was prepared via protocol 1, using 31(iv) (50 mg, 0.11mmol) and (D)-lys(BOC)-OMe (68 mg, 0.23 mmol) to yield the desiredproduct 32(i) as an off white solid (90 mg, 87%). R_(f)=0.44 (5%MeOH/DCM).

¹H NMR (300 MHz, CDCl₃) δ 1.18, m, 4H, 1.40, m, 4H, 1.43, s, 18H, 1.69,m, 12H, 3.01, m, 4H, 3.73, s, 6H, 3.87, m, 2H, 4.15, m, 2H, 4.47, m, 2H,4.53, m, NH; 5.62, d, J=8.2 Hz, NH; 7.19, m, 2H, 7.22, m, 2H, 7.35, m,2H, 7.45, d, J=9.1 Hz, 2H, 7.91, d, J=8.2 Hz, 2H, 7.99, d, J=8.8 Hz, 2H.MS (ES +ve) m/z 981.5 (30%) [M+K]⁺; 968.6 (100) [M+Na]⁺; 943.6 (10)[M+H]⁺.

This compound was prepared via Protocol 3, using 32(i) (88 mg, 0.093mmol) to yield the desired product 32 as an off white solid (50 mg,76%).

¹H NMR (300 MHz, CD₃OD) δ 1.39, m, 4H, 1.67, m, 12H, 1.96, m, 4H, 2.89,m, 4H, 3.35, s, 6H, 4.02, m, 4H, 4.30, m, 2H, 7.02, dist d; J=8.0 Hz,2H, 7.17, m, 2H, 7.29, m, 2H, 7.52, m, 2H, 7.87, m, 2H, 7.98, m, 2H. MS(ES +ve) m/z 743.3 (10%) [M+H]⁺; 372.6 (100) [M+2H]²⁺.

Synthesis of Compound 33

This compound was prepared via Protocol 1, using (D)-arg(Pmc)-OMe (40mg, 0.088 mmol) and 31(iv) (20 mg, 0.044 mmol) to yield 33(i) as a whitesolid (18 mg, 31%).

¹H NMR (300 MHz, CDCl₃) δ 1.28, s, 12H, 1.43, m, 4H, 1.77, m, 12H, 1.86,m, 4H, 2.09, s, 6H, 2.52, s, 6H, 2.55, s, 6H, 2.59, m, 2H, 3.12, m, 4H,3.65, s, 6H, 3.84, m, 2H, 4.01, m, 2H, 4.37, m, 2H, 6.20, br s, NH;6.42, m, NH; 7.02, dist d, NH; 7.09, d, J=8.3 Hz, 2H, 7.19, dist t, 2H,7.30, dist t, 2H, 7.39, d, J=9.1 Hz, 2H, 7.85, m, 2H, 7.92, d, J=9.1 Hz,2H, 7.97, d, NH; 7.99, d, NH.

This compound was prepared via Protocol 3, using 33(i) (20 mg, 0.015mmol) to yield 33 as a white solid (9 mg, 64%).

¹H NMR (300 MHz, CD₃OD) δ 1.34, m, 10H, 1.61, m, 6H, 2.93, m, 4H, 3.46,s, 6H, 3.62, m, 2H, 3.75, m, 2H, 4.05, m, 2H, 6.53, m, 2H, 6.74, m, 4H,7.16, d, J=8.8 Hz, 2H, 7.42, d, J=7.7 Hz, 2H, 7.57, d, J=8.3 Hz, 2H. MS(ES +ve) m/z: 401 (100%) [M+2H]²⁺.

Synthesis of Compound 34

To 32(i) (200 mg, 0.212 mmol) dissolved in THF (20 ml), was added asolution of LiOH (75 mg, 3.14 mmol) in water (10 ml). After stirring atRT for 90 minutes, ethyl acetate was added and the layers separated. Theaqueous layer was then acidified with a dilute potassium bisulphatesolution. This was then extracted with DCM (3×20 ml) and the combinedorganic extracts then dried and evaporated to dryness to yield theproduct 34(i) as a white foamy solid (178 mg, 92%).

¹H NMR (300 MHz, CDCl₃) δ 1.24, m, 4H, 1.40, s, 18H, 1.44, m, 4H, 1.76,m, 12H, 3.00, m, 4H, 3.77, m, 2H, 4.09, m, 2H, 4.46, m, 2H, 4.85, m, NH;6.29, m, NH; 7.16, m, 2H, 7.21, m, 2H, 7.28, m, 2H, 7.30, d, J=9.0 Hz,2H, 7.84, d, J=7.8 Hz, 2H, 7.87, d, J=8.7 Hz, 2H. MS (ES +ve) m/z 937.2(15%) [M+Na]⁺; 915.2 (15) [M+H]⁺. MS (ES −ve) m/z 913.1 (100%) [M−H]⁻.

This compound was prepared via Protocol 4, using 34(i) (120 mg, 0.131mmol), triphenyl phosphine (73 mg, 0.278 mmol), DIAD (0.055 ml, 0.275mmol) and BzOH (0.05 ml, 0.275 mmol). The BOC-protected intermediate34(ii) eluted at the same time as a reaction by product, and so thismaterial was then deprotected via protocol 3 to yield the desiredproduct 34 as a pale yellow hydrochloride salt (101 mg, 80%).

¹H NMR (300 MHz, CDCl₃) δ 1.32, m, 4H, 1.68, m, 10H, 1.79, m, 2H, 1.93,m, 4H, 2.82, m, 4H, 3.97, m, 4H, 4.33, m, 2H, 5.11, ABq, J=12.3 Hz, 4H,7.01, dist d, J=8.5 Hz, 2H, 7.14, app t, 2H, 7.31, m, 14H, 7.48, m, 2H,7.62, m, 2H, 7.85, d, J=7.9 Hz, 2H, 7.94, d, J=8.8 Hz, 2H. MS (ES +ve)m/z 895.5 (10%) [M+H]⁺; 825.4 (40) [M-lys]⁺; 448.7 (100) [M+2H]²⁺.

Synthesis of Compound 35

This compound was prepared via Protocol 4, using 34(i) (60 mg, 0.066mmol), triphenylphosphine (73 mg, 278 mmol), DIAD (0.055 ml, 0.275 mmol)and 1-naphthalene methanol (45 mg, 0.0.28 mmol). The BOC-protectedintermediate 35(i) eluted at the same time as a reaction by product, andso this material was then deprotected via Protocol 3 to yield thedesired product 35 as a pale yellow hydrochloride salt (58 mg, 83%).

¹H NMR (500 MHz, CDCl₃) δ 1.10, m, 4H, 1.40, m, 4H, 1.51, m, 4H, 1.63,m, 4H, 1.76, m, 4H, 2.58, m, 4H, 3.73, m, 2H, 3.80, m, 2H, 4.19, m, 2H,6.90, dist t, 2H, 7.00, t, J=7.1 Hz, 2H, 7.13, dist t, 2H, 7.30, m, 4H,7.37, m, 6H, 7.38, m, 8H, 7.84, d, J=8.0 Hz; 2H. MS (ES +ve) m/z 995.5(10%) [M+H]⁺; 825.4 (40) [M-lys]⁺; 448.7 (100) [M+2H]²⁺.

Synthesis of Compound 36

The crude PMC protected precursor 36(i) was prepared via Protocol 1using 34(i) (120 mg, 0.131 mmol) and 2-pyridyl carbinol (0.026 ml) toyield an impure light brown solid. This was then deprotected viaprotocol 3 to yield 36 as an off white solid (68 mg, 54%).

¹H NMR (300 MHz, CD₃OD) δ 1.41, m, 4H, 1.65, m, 8H, 1.95, m, 4H, 2.87,m, 4H, 3.97, m 4H, 4.31, m, 2H, 5.41, ABq, J=14.4 Hz, 2H, 5.52, ABq,J=14.4 Hz, 2H, 6.96, dist d, 2H, 7.14, dist t, 2H, 7.26, dist t, 2H,7.46, dist d, 2H, 7.83, d, J=7.9 Hz, 2H, 7.92, m, 4H, 8.00, dist d, 2H,8.47, dist t 2H, 8.76, br d, 2H. MS (ES +ve) m/z 449.4 (100%) [M+2H]²⁺.

Synthesis of Compound 37

To 33(i) (200 mg, 0.2 mmol) dissolved in THF (20 ml), was added asolution of LiOH (75 mg, 3.1 mmol) in water (10 ml). After stirring atRT for 90 minutes, ethyl acetate was added and the layers separated. Theaqueous layer was then acidified with a dilute potassium bisulphatesolution. This was then extracted with DCM (3×20 ml) and the combinedorganic extracts then dried and evaporated to dryness to yield theproduct 37(i) as a white foamy solid (145 mg, 88%). The protectedprecursor was prepared via Protocol 1 using 37(i) (60 mg, 0.046 mmol)and 2-pyridyl carbinol (0.02 ml) to yield 37(ii) as an impure lightbrown solid (MS (ES +ve) m/z 1485.5 (10%) [M+H]⁺; 743.3 (20) [M+H]²⁺).This was then deprotected via Protocol 3 to yield 37 as an off whitesolid (28 mg, 64%).

¹H NMR (300 MHz, CD₃OD) δ 1.69, m, 10H, 2.00, m, 6H, 3.20, m, 4H, 4.00,m, 4H, 4.39, m, 2H, 5.44, ABq, J=14.9 Hz, 2H, 5.53, ABq, J=14.9 Hz, 2H,6.99, m, 2H, 7.16, m, 2H, 7.28, m, 2H, 7.50, m, 2H, 7.94, m, 8H, 8.47,m, 2H, 8.78, m, 2H. MS (ES +ve) m/z 477.5 (100%) [M+2H]²⁺.

Synthesis of Compound 38

To a suspension of (R)-1,1′-binapth-2,2′-ol (1 g, 3.5 mmol) andanhydrous potassium carbonate (2.4 g, 5 equiv) dissolved in acetone (25ml), was added ethyl bromobutyrate (1.15 ml, 2.3 equivalents) under anN₂ atmosphere. The mixture was then heated at reflux for 4 days beforebeing evaporated to dryness and the residue partitioned between ethylacetate and water. The organic layer was then washed twice with waterbefore being dried and evaporated to dryness. The crude residue wassubjected to flash column chromatography to yield the desired compound38(i) (1.05 g, 68%).

¹H NMR (300 MHz, CDCl₃) δ 1.15, t, J=7.2 Hz, 6H, 1.70, m, 4H, 1.86, m,4H, 3.98, m, 8H, 7.16, m, 4H, 7.27, m, 2H, 7.38, d, J=9.1 Hz, 2H, 7.82,d, J=8.2 Hz, 2H, 7.90, d, J=9.1 Hz, 2H.

To 38(i) (1.0 g, 1.94 mmol) dissolved in THF (30 ml), was added asolution of LiOH (300 mg, 12.5 mmol) in water (20 ml), After stirring atRT overnight, diethyl ether was added and the layers separated. Theaqueous layer was then acidified with a dilute HCl solution. This wasthen extracted with diethyl ether (3×20 ml), the combined organicextracts were then dried and evaporated to dryness to yield 38(ii) as awhite foamy solid (646 mg, 89%).

¹H NMR (300 MHz, CDCl₃) δ 1.71, m, 4H, 1.90, m, 4H, 3.91, m, 2H, 3.99,m, 2H, 7.11, dist d, J=8.3 Hz, 2H, 7.18, m, 2H, 7.27, m, 2H, 7.37, d,J=8.8 Hz, 2H, 7.83, d, J=8.0 Hz, 2H, 7.90, d, J=8.8 Hz, 2H, 9.34, bs s,COOH.

This compound was prepared via Protocol 1, using 31(ii) (125 mg, 0.236mmol) and 38(ii) (45 mg, 0.098 mmol) to yield 38(iii) as a white solid(123 mg, 86%).

¹H NMR (300 MHz, CDCl₃) δ 1.25, s, 12H, 1.34, m, 4H, 1.70, m, 16H, 2.06,s, 6H, 2.51, m, 16H, 3.04, m, 4H, 3.79, m, 2H, 3.96, m, 2H, 4.37, m, 2H,5.04, s, 4H, 6.05, br s, NH; 6.21, br s, NH; 7.06, d, J=8.5 Hz, 2H,7.15, dist t, 2H, 7.25, m, 12H, 7.32, d, J=9.1 Hz; 2H, 7.79, d, J=7.9Hz, 2H, 7.87, d, J=9.1 Hz, 2H. MS (ES +ve) m/z 1483.4 (10%) [M+H]⁺;742.4 (20) [M+H]²⁺.

This compound was prepared via Protocol 3, using 38(iii) (120 mg, 0.081mmol) to yield 38 as a white solid (71 mg, 86%).

¹H NMR (300 MHz, CD₃OD) δ 1.56, m, 4H, 1.67, m, 6H, 1.83, m, 2H, 1.93,m, 4H, 3.12, m, 4H, 3.93, m, 2H, 4.02, m, 2H, 4.34, m, 2H, 5.07, ABq,J=12.3 Hz, 2H, 5.12, ABq, J=12.3 Hz, 2H, 7.00, m, 2H, 7.12, m, 2H, 7.27,m, 12H, 7.46, m, 2H, 7.83, d, J=7.9 Hz, 2H, 7.93, d, J=9.1 Hz, 2H. MS(ES +ve) m/z 476.5 (100%) [M+H]²⁺.

Synthesis of Compound 39

To 34 (20 mg, 0.021 mmol) in DCM (2 ml) was added triethylamine (0.09ml) and N,N′-bis(tert-butoxycarbonyl)-N″-triflyl guanadine (25 mg, 0.062mmol) under N₂. The solution was allowed to stir overnight before beingevaporated to dryness. The resultant residue was then subjected to flashcolumn chromatography (over silica), using 2% MeOH/DCM as the eluant toyield the desired compound 39(i) as a pale yellow oil (23 mg, 79%).

¹H NMR (300 MHz, CDCl₃) δ 1.18, m, 4H, 1.48, m, 40H, 1.59, m, 4H, 1.70,m, 8H, 3.27, m, 4H, 3.82, m, 2H, 4.09, m, 2H, 4.45, m, 2H, 5.15, ABq,J=12.3 Hz, 4H, 5.54, d, J=8.2 Hz, NH; 7.16, dist d, J=8.2 Hz, 2H, 7.24,m, 2H, 7.31, m, 11H; 7.49, m, 1H, 7.62, m, 2H, 7.87, d, J=7.9 Hz, 2H,7.94, d, J=9.1 Hz, 2H, 8.28, m, NH. MS (ES +ve) m/z 1401.7 (40%)[M+Na]⁺; 1379 (100) [M+H]⁺.

This compound was prepared via Protocol 3, using 39(i) (20 mg, 0.014mmol) to yield the desired product 39 as a light brown solid (15 mg,86%).

¹H NMR (300 MHz, CDCl₃) δ 1.18, m, 4H, 1.48, m, 40H, 1.59, m, 4H, 1.70,m, 8H, 3.27, m, 4H, 3.82, m, 2H, 4.09, m, 2H, 4.45, m, 2H, 5.15, ABq,J=12.3 Hz, 4H, 5.54, d, J=8.2 Hz, NH; 7.16, dist d, J=8.2 Hz, 2H, 7.24,m, 2H, 7.31, m, 11H, 7.49, m, 1H, 7.62, m, 2H, 7.87, d, J=7.9 Hz, 2H,7.94, d, J=9.1 Hz, 2H, 8.28, m, NH. MS (ES +ve) m/z 490.5 (60%)[M+2H]²⁺; 452.4 (100) [M+H-Ph]²⁺; 414.5 (80) [M+2H-2Ph]²⁺.

Synthesis of Compound 40

To 35 (47 mg, 0.044 mmol) in DCM (2 ml) was added triethylamine (0.19ml) and N,N′-bis(tert-butoxycarbonyl)-N″-triflylguanadine (53 mg, 0.13mmol) under N2. The solution was allowed to stir overnight before beingevaporated to dryness. The resultant residue was then subjected to flashcolumn chromatography (over silica), eluting with 2% MeOH/DCM to yieldthe desired compound 40(i) as an off white solid (40 mg, 61%).

¹H NMR (300 MHz, CDCl₃) δ 1.01, m, 2H, 1.32, m, 2H, 1.48, m, 44H, 1.54,m, 4H, 1.70, m, 8H, 3.14, m, 4H, 3.73, m, 2H, 4.00, m, 2H, 4.42, m, 2H,5.51, d, J=7.9 Hz, NH; 5.61, ABq, J=12.3 Hz, 4H, 7.12, dist d, J=7.9 Hz,2H, 7.26, m, 6H, 7.53, m, 8H, 7.80, m, 4H, 7.88, m, 4H, 7.97, dist d,J=7.9 Hz, 2H, 8.24, m, NH. MS (ES +ve) m/z 1501.8 (10%) [M+Na]⁺; 1479.7(10) [M+H]⁺; 740.5 (20) [M+2H]²⁺.

This compound was prepared via Protocol 3, using 40(i) (38 mg, 0.026mmol) to yield the desired product 40 as a light brown solid (18 mg,61%).

¹H NMR (300 MHz, CDCl₃) δ 1.32, m, 6H, 1.62, m, 10H; 1.92, m, 4H, 2.95,m, 2H, 3.10, m, 2H, 3.97, m, 4H, 4.30, m, 2H, 5.57, m, 4H, 7.02, m, 2H,7.17, m, 2H, 7.229, m, 2H, 7.50, m, 10H, 7.88, m, 10H. MS (ES +ve) m/z540.4 (20%) [M+2H]²⁺; 477.3 (95) [M+H-nap]²⁺; 414.4 (100) [M+H-2nap]²⁺.

Compounds of Formula III

Synthesis of Compound 41

To a suspension of 3-aminobenzoic acid (1.03 g mg, 7.52 mmol) in MeOH(80 ml) at 0° C. was added dropwise thionyl chloride (5 ml). Theresulting solution was allowed to stir for 16 h before the solvent wasremoved by evaporation and the product precipitated with diethyl ether.The diethyl ether was removed by evaporation to yield the title compound41(i) as a white solid (1.38 g, 98%). Mp 176-178° C.

¹H NMR (300 MHz, D₂O) δ 3.66, s, 3H, 7.37, m, 1H, 7.42, m, 1H, 7.71, m,1H, 7.75, dt, J=1.8, 3.3, 7.2 Hz, 1H. MS (CI) m/z 152 (100%) [M]⁺.

This compound was prepared via Protocol 1, from 41(i) (220 mg, 2.27mmol) and (R)-Fmoc-Lys(Boc)-OH (578 mg, 1.27 mmol) to afford 41(ii) as awhite solid (277 mg, 36%). Mp 96-98° C.

¹H NMR (300 MHz, CDCl₃) δ 1.42, s, 9H, 1.60, m, 2H, 1.78, m, 2H, 3.08,m, 2H, 3.86, s, 3H, 4.17, t, J=6.9 Hz, 1H, 4.36, d, J=6.9 Hz, 2H, 4.63,m, 1H, 6.03, d, J=8.1 Hz, 2H, 7.26, m, 2H, 7.36, m, 2H, 7.56, d, J=7.2,Hz, 2H, 7.72, d, J=7.8 Hz, 2H, 7.77, m, 1H, 7.88, d, J=8.1 Hz, 1H, 8.17,s, 1H, 9.15, s, 1H. MS (ES +ve) m/z 610 (100%) [M+Na]⁺; 588 (70) [M+H]⁺.

This compound was prepared via Protocol 2, from 41(ii) (555 mg, 0.95mmol) to yield 41(iii) as a colourless viscous oil (285 mg, 82%).

¹H NMR (300 MHz, CDCl₃) δ 1.43, s, 9H, 1.65, m, 4H, 2.08, m, 2H, 3.19,m, 2H, 3.69, m, 1H, 3.91, s, 3H, 5.11, m, 1H, 7.36, m, 1H, 7.51, t,J=7.8 Hz, 1H, 7.84, t, J=1.8 Hz, 1H, 8.04, m, 1H. MS (ES +ve) m/z 264(100%) [M-Boc+H]⁺.

This compound was prepared via Protocol 1, from 22(ii) (288 mg, 0.75mmol) and 41(iii) (275 mg, 0.75 mmol) to afford 41(iv) as a white foam(434 mg, 79%). Mp 70° C.

¹H NMR (300 MHz, CDCl₃) δ 1.04, m, 2H, 1.44, s, 9H, 1.62, m, 2H, 2.96,m, 2H, 3.87, s, 3H, 4.55, m, 5H, 4.94, m, 2H, 5.69, m, 1H, 6.45, d,J=8.1 Hz, 1H, 7.85, m, 8H, 7.91, m, 7H, 9.08, s, 1H. MS (ES +ve) m/z 732(50%) [M+H]⁺; 351 (100).

This compound was prepared via Protocol 3, from 41(iv) (56 mg, 0.077mmol) to yield 41 as a highly hydroscopic cream solid (38 mg, 74%).

¹H NMR (300 MHz, CD₃OD) δ 1.30, m, 2H, 1.67, m, 2H, 2.76, m, 2H, 3.93,s, 3H, 4.59, m, 5H, 4.90, m, 2H, 5.71, m, 1H, 7.06, m, 2H, 7.34, m, 8H,7.75, m, 2H, 7.92, m, 2H, 8.02, m, 2H. MS (ES +ve) m/z 632 (100%) [M]⁺.

Synthesis of Compound 42

To a solution of 41(iv) (370 mg, 0.51 mmol) in THF/water, 3:1 (8 ml) wasadded lithium hydroxide monohydrate (43 mg, 0.51 mmol) and the resultingsuspension was allowed to stir for 16 h. The reaction mixture wasdiluted with water (30 ml) and the THF was removed by evaporation beforethe remaining aqueous layer was washed with diethyl ether (40 ml) toremove unreacted starting material. The aqueous phase was acidified withdilute potassium bisulfate and the resulting precipitate was extractedwith DCM (3×40 ml). The combined DCM fractions were dried and evaporatedto yield the title compound 42(i) as a white solid (350 mg, 96%). Mp86-90° C.

¹H NMR (300 MHz, CDCl₃) δ 1.15, m, 2H, 1.49, s, 9H, 1.65, m, 2H, 3.03,m, 2H, 4.59, m, 5H, 5.01, m, 2H, 5.71, m, 1H, 6.63, d, J=9.0 Hz, 1H,7.34, m, 8H, 7.97, m, 7H, 9.26, s, 1H, 9.70, br s, 1H. MS (ES +ve) m/z740 (100%) [M+Na]⁺; 718 (20) [M+H]⁺.

To a solution of 42(i) (40 mg, 0.056 mmol) in acetone (2 ml) was addedK₂CO₃ (17 mg, 0.12 mmol) and benzyl bromide (21 mg, 0.12 mmol). Theresulting suspension was allowed to stir for 16 h before concentrationand purification by flash column chromatography (5% MeOH/DCM) to yieldthe title compound 42(ii) as a white solid (36 mg, 80%). Mp 145-152° C.

¹H NMR (300 MHz, CDCl₃) δ 1.05, m, 2H, 1.42, s, 9H, 1.52, m, 2H, 3.00,m, 2H, 4.50, m, 5H, 4.87, m, 2H, 5.30, s, 2H, 5.68, m, 1H, 6.27, d,J=8.4 Hz, 1H, 7.30, m, 11H; 7.90, m, 7H, 8.63, s, 1H. MS (ES +ve) m/z808 (30%) [M+H]⁺; 414 (100%).

This compound was prepared via Protocol 3, from 42(ii) (35 mg, 0.043mmol) to yield 42 as a highly hydroscopic cream solid (30 mg, 93%).

¹H NMR (500 MHz, CD₃OD) δ 1.22, m, 2H, 1.59, m, 2H, 2.68, m, 2H, 4.46,m, 5H, 4.79, m, 2H, 5.27, s, 2H, 5.58, m, 1H, 7.28, m, 11H; 7.80, m, 7H,8.25, s, 1H. MS (ES +ve) m/z 750 (35%) [M+K]⁺; 360 (100%).

Synthesis of Compound 43

This compound was prepared via Protocol 1, from 42(i) (91 mg, 0.127mmol) and O-benzylhydroxylamine (20 mg, 1.27 mmol) to afford 43(i) as awhite solid (82 mg, 78%). Mp 141-144° C.

¹H NMR (300 MHz, CDCl₃) δ 1.06, m, 2H, 1.43, s, 9H, 1.54, m, 2H, 2.93,m, 2H, 4.30, m, 1H, 4.54, m, 4H, 4.66, t, J=5.1 Hz, 1H, 4.95, m, 4H,5.66, m, 1H, 6.41, d, J=7.5 Hz, 1H, 7.31, m, 10H, 7.88, m, 2H, 7.97, m,2H, 9.14, s, 1H. MS (ES +ve) m/z 823 (100%) [M+H]⁺.

This compound was prepared via Protocol 3, from 43(i) (73 mg, 0.089mmol) to yield 43 as a hydroscopic white solid (67 mg, 99%).

¹H NMR (500 MHz, CD₃OD) δ 1.15, m, 2H, 1.62, m, 2H, 3.23, m, 2H, 3.90,m, 1H, 4.46, m, 6H, 4.90, m, 2H, 5.63, m, 1H, 7.50, m, 20H. MS (ES +ve)m/z 723 (20%) [M]⁺; 360 (100%).

Synthesis of Compound 44

To a solution of 41 (32 mg, 0.048 mmol) in DCM (3 ml) was addedN1-tert-butoxycarboxamido(trifluoromethylsulfonylimino)methylpropanamide (28 mg, 0.072 mmol), triethylamine (7.3 mg, 0.072 mmol). Theresulting solution was allowed to stir for 16 h under a nitrogenatmosphere. The solvent was evaporated and the crude product waspurified by flash column chromatography (15:1, DCM/MeOH) to yield thetitle compound 44(i) as a white solid (41 mg, 98%). Mp 74-76° C.

¹H NMR (300 MHz, CDCl₃) δ 1.14, m, 2H, 1.46, s, 9H, 1.51, s, 9H, 1.65,m, 2H, 3.26, m, 2H, 3.91, s, 3H, 4.34, m, 1H, 4.48, m, 2H, 4.57, d,J=3.3 Hz, 2H, 4.67, m, 2H, 5.59, m, 1H, 6.34, d, J=8.4 Hz, 1H, 7.26, m,8H, 7.77, m, 7H, 8.27, br s, 1H, 8.55, s, 1H. MS (ES +ve) m/z 896 (100%)[M+Na]⁺; 875 (95%) [M+H]⁺.

This compound was prepared via Protocol 3, from 44(i) (49 mg, 0.056mmol) to yield 44 as a cream solid (32 mg, 0.045 mmol, 80%). Mp 124-126°C.

¹H NMR (300 MHz, CD₃OD) δ 1.17, m, 2H, 1.63, m, 2H, 3.01, m, 2H, 3.92,s, 3H, 4.52, m, 5H, 4.97, m, 2H, 5.73, m, 1H, 7.07, m, 2H; 7.32, m, 9H,7.90, m, 4H, 8.28, s, 1H. MS (ES +ve) m/z 698 (25%) [M+Na]⁺; 413 (100%).

Synthesis of Compound 45

To a solution of 42 (20 mg, 0.027 mmol) in DCM (2 ml) was addedN1-tert-butoxycarboxamido(trifluoromethylsulfonylimino)methylpropanamide (16 mg, 0.041 mmol), and triethylamine (4 mg, 0.041 mmol).The resulting solution was allowed to stir for 16 h under N₂. Thesolvent was evaporated and the crude product was purified by flashcolumn chromatography (15:1, DCM/MeOH) to yield the title compound 45(i)as a white solid (15 mg, 58%). Mp 122-126° C.

¹H NMR (300 MHz, CDCl₃) δ 1.15, m, 2H, 1.46, s, 9H, 1.50, s, 9H, 1.63,m, 2H, 3.25, m, 2H, 4.32, m, 1H, 4.45, m, 2H, 4.56, m, 2H, 4.85, m, 2H,5.37, s, 2H, 5.56, m, 1H, 6.31, d, J=8.1 Hz, 1H, 7.32, m, 8H, 7.85, m,7H, 8.26, br s, 1H, 8.41, s, 1H. MS (ES +ve) m/z 950 (100%) [M+H]⁺.

This compound was prepared via Protocol 3, from 45(i) (15 mg, 0.016mmol) to yield 45 as a highly hydroscopic cream solid (6 mg, 48%).

¹H NMR (500 MHz, CD₃OD) δ 1.08, m, 2H, 1.54, m, 2H, 2.92, m, 2H, 4.28,dd, J=5.0, 7.0 Hz, 1H, 4.47, m, 4H, 4.80, m, 2H, 5.27, s, 2H, 5.59, m,1H, 7.25, m, 13H, 7.79, m, 7H, 8.22, s, 1H. MS (ES +ve) m/z 750 (100%)[M]⁺.

Synthesis of Compound 46

To a solution of 43 (51 mg, 0.067 mmol) in DCM (3 ml) was addedN1-tert-butoxycarboxamido(trifluoromethylsulfonylimino)methylpropanamide (39 mg, 0.10 mmol), and triethylamine (0.1 ml). Theresulting solution was allowed to stir for 16 hr under N₂. The solventwas evaporated and the crude product was purified by flash columnchromatography (15:1, DCM/MeOH) to yield the title compound 46(i) as awhite solid (58 mg, 90%). Mp 112° C.

¹H NMR (300 MHz, CDCl₃) δ 1.10, m, 2H, 1.44, s, 9H, 1.50, s, 9H, 1.65,m, 2H, 3.23, m, 2H, 4.25, m, 1H, 4.51, m, 4H, 4.89, m, 2H, 5.00, s, 2H,5.63, m, 1H, 6.34, d, J=7.5 Hz, 1H, 7.31, m, 16H, 7.90, m, 4H, 8.25, brs, 1H, 9.05, s, 1H. MS (ES +ve) m/z 987 (100%) [M+Na]⁺; 965 (90%)[M+H]⁺.

This compound was prepared via Protocol 3, from 46(i) (16 mg, 0.017mmol) to yield 46 as a cream solid (7 mg, 51%). Mp 142-C.

¹H NMR (300 MHz, CD₃OD) δ 1.20, m, 2H, 1.66, m, 2H, 3.04, m, 2H, 3.97,m, 1H, 4.49, m, 6H, 4.96, m, 2H, 5.60, m, 1H, 7.33, m, 16H, 7.95, m, 4H.MS (ES +ve) m/z 765 (20%) [M]⁺; 102 (100).

Synthesis of Compound 47

To a solution of 43(i) (28 mg, 0.034 mmol) in THF (3 ml) was addedpalladium on activated carbon (15 mg). The resulting mixture was flushedwith hydrogen gas and allowed to stir for 16 h. The mixture was filteredthrough celite and evaporated to dryness. This intermediate product wasthen subjected to the Protocol 3 to yield the title compound 47 as awhite solid (16 mg, 70%). Mp 116° C.

¹H NMR (500 MHz, CD₃OD) δ 0.76, m, 3H, 1.35, m, 4H, 1.67, m, 2H, 3.66,m, 2H, 3.88, m, 2H, 4.08, m, 1H, 4.56, m, 2H, 7.30, m, 9H, 7.89, m, 5H.MS (ES +ve) m/z 636 (50%) [M]⁺; 623 (100).

Synthesis of Compound 48

To a solution of 46(i) (39 mg, 0.040 mmol) in THF (3 ml) was addedpalladium on activated carbon. The resulting mixture was flushed withhydrogen gas and allowed to stir for 16 h. The mixture was filteredthrough celite and evaporated to dryness. This intermediate product wasthen subjected to Protocol 3 to yield the title compound 48 as a whitesolid (24 mg, 84%). Mp 158-160° C.

¹H NMR (300 MHz, CD₃OD) δ 0.51, t, J=7.2 Hz, 3H, 1.17, m, 2H, 1.40, m,2H, 1.62, m, 2H, 3.03, m, 2H, 3.92, m, 2H, 4.09, m, 1H, 4.45, ABq,J=14.1 Hz, 2H, 7.24, m, 9H, 7.95, m, 5H, 9.96, br s, 1H. MS (ES +ve) m/z677 (100%) [M]⁺.

Activity

Antibacterial Assay Method for Staphylococcus aureus (ATCC 6538P) andEnterococcus faecium

Bacterial Strains:

Staphylococcus aureus (ATCC 6538P)

Enterococcus faecium

VRE strains: #243 E. faecium van B ST17 #449 E. faecium van B ST17

#820 E. faecium van A ST17 #987 E. faecium van B ST39

The S. aureus assay is performed in the PC2 lab and the E. faecium assayis performed in the PC3 lab.

Compound Preparation:

Compounds are accurately weighed out (between approx. 1-2 mg) anddissolved in either 10% methanol/water (v/v) or 100% DMSO to a finalstock concentration of 5 mg/ml.

Compounds are then diluted 1/10 in H₂O to a test conc of 500 ug/ml readyfor immediate use, or storage at −20° C.

Starter Culture:

Grow up an o/n starter culture of Staphylococcus aureus and each VREstrain by diluting previous culture (stored at 4° C.) 1/1000 into −50mls Luria Broth (LB) for S. aureus or Enterococossel Broth (EB) for theVRE strains.

Incubate o/n at 37° C.+shaking.

-   -   A glycerol stock (0.6 mls bacterial culture, 0.3 mls glycerol)        of each strain is kept at −80° C. if needed.        Assay Set Up:

In a 96well round bottom plate add 50 ul LB/well for the S. aureus plateand add 50 ul EB/well for the VRE plates.

Add 50 ul of compound dilution (500 ug/ml test conc) to each of threetop row wells (ie: tested in triplicate) and dilute 1 in 2 from the toprow to the bottom row.

After the compound dilution, add to each well 50 ul of a 1/1000 dilutionof the appropriate overnight bacterial culture, either S. aureus or thedifferent VRE strains.

Plates are incubated at 37° C. on a slowly rotating plate incubator.

-   -   test concentrations are (in ug/ml) 125, 62.5, 31.25, 15.6, 7.8,        3.9, 1.9, 0.98    -   final DMSO concentration in the first row of wells of the assay        is 2.5%    -   Vancomycin is included in the assay (in triplicate) at a        starting test concentration of 5 ug/ml for S. aureus and 125        ug/ml for the VRE strains        Reading Results of Assay:

After incubation for 24 hrs the plates are removed and read. Inhibitionof bacterial growth is indicated by lack of bacterial pellet or a clearwell. In the VRE plates bacterial growth is indicated by black colouredmedia (EB) as well as a bacterial pellet.

Untreated control wells are included in the assay to check they allcontain bacterial pellets. Uninoculated untreated control wells areincluded to check they all contain clear medium.

The plates are analysed for MIC and the results tabulated.

Antibacterial Assay Results for Staphylococcus Aureus (ATCC 6538P) andEnterococcus faecium

Activity for Compounds was determined in the assays described. Theminimum inhibitory concentration (μg/ml) was determined to be in a givenrange if at least two of three values fell within that range.

-   -   MIC of the compound in the range of less than 0.98 (μg/ml) is        designated in the table by ++++    -   MIC of the compound in the range of greater than or equal to        0.99 (μg/ml) and less than or equal to 15.6 (μg/ml) is        designated in the table by +++    -   MIC of the compound in the range of greater than or equal to        15.7 (μg/ml) and less than or equal 62.5 (μg/ml) is designated        in the table by ++    -   MIC of the compound in the range of greater than or equal to        62.6 (μg/ml) is designated in the table by +

Compound Sa 243 449 820 987 Van +++ ++++ ++ + ++++  1 +++ ++ ++ +++ ++ 2 +++ ++ ++ ++ ++  3 +++ ++ ++ ++ ++  4 +++ ++ ++ ++ ++  5 +++ ++ ++ ++++  6 +++ ++ ++ ++ ++  7 +++ ++ ++ ++ ++  8 ++ + + + +  9 +++ + ++ ++ ++10 +++ ++ ++ ++ ++ 11 +++ ++ ++ ++ ++ 12 +++ ++ +++ ++ ++ 13 +++ ++ ++++ ++ 14 +++ ++ ++ ++ + 15 +++ ++ ++ ++ ++ 16 +++ + + + + 17 ++++ ++ ++++ ++ 18 +++ ++ ++ ++ ++ 19 +++ ++ ++ ++ ++ 20 +++ ++ ++ ++ ++ 21 +++ ++++ ++ ++ 22 +++ ++ ++ ++ ++ 23 +++ ++ ++ ++ ++ 24 +++ ++ ++ ++ ++ 25 +++++ ++ ++ ++ 26 +++ ++ ++ ++ ++ 27 +++ ++ ++ ++ + 28 +++ ++ ++ ++ ++ 29+++ ++ +++ +++ ++ 30 +++ + + + + 31 +++ ++ ++ ++ ++ 32 + + + + + 33+++ + + 34 +++ + ++ ++ + 35 +++ + + ++ + 36 + + + + + 37 +++ + + + + 38+++ ++ ++ ++ ++ 39 +++ + ++ ++ + 40 +++ + + ++ + 41 +++ + + + + 42++ + + + + 43 +++ + + ++ + 44 +++ + + ++ + 45 +++ ++ ++ ++ ++ 46+++ + + + + 47 +++ + + + +Antibacterial Assay Methods for Staphylococcus aureus Mu50 (ATCC700699), Methicillin-Resistant Staphylococcus aureus (ATCC 43300),Multi-Drug-Resistant Staphylococcus epidermidis (ATCC 700562) Compounds

The compounds were stored at room temperature in the dark prior to use.Each compound was solubilized in DMSO to a final concentration of 40mg/mL. The stock material was diluted to a concentration equivalent totwo times the final in-well high test concentration (100 μg/mL for allexperimental compounds) in Mueller Hinton II broth. Precipitation wasobserved in the wells at 100 and 50 μg/mL with all eight compounds.Vancomycin and oxacillin were obtained from Sigma Aldrich ChemicalCompany and were used as positive and/or negative control compounds inthe reported assays at high test concentrations of 100, 25 and 100 μg/mLrespectively.

Bacterial Strains

The bacterial strains employed in these assays were obtained from theAmerican Type Culture Collection (ATCC). All of the bacterial strainswere propagated as recommended by the ATCC. Each strain was stored as afrozen glycerol stock at −80° C. and a 10 μL loop of the frozen stockswas used to inoculate each culture for these assays. The strains withtheir classification and properties are listed in the table below.

Bacteria Strain ATCC # Classification Properties Staphylococcus 700699Gram Positive Mu50, Reduced aureus Vancomycin SusceptibilityStaphylococcus 43300 Gram Positive Methicillin-Resistant aureusStaphylococcus 700562 Gram Positive Multi-Drug-Resistant epidermidisMIC Determination

The susceptibility of the above microorganisms to the test compounds wasevaluated by determining the MIC of each compound using micro-brothdilution analysis according to the methods recommended by the NCCLS. Allmicrobial strains were obtained from American Type Culture Collections(ATCC) and cultured according to the suppliers recommendations.Evaluation of the susceptibility of each organism against the testcompounds included a positive control antibiotics Vancomycin andOxacillin. For each organism, a standardized inoculum was prepared bydirect suspension of freshly plated colonies in Mueller Hinton II brothto an optical density 625 nm (OD₆₂₅) of 0.1 (equivalent to a 0.5McFarland standard). The suspended inoculum was diluted to aconcentration of approximately 1×10⁶ colony forming units per milliliter(CFU/mL) and 100 μL placed into triplicate wells of a 96-well platecontaining 100 μL of test compound serially diluted 2-fold in MuellerHinton II broth. One hundred microliters of the inoculum was also addedto triplicate wells containing 100 μL of two-fold serial dilutions of apositive control antibiotic and to wells containing 100 μL of mediaonly. This dilution scheme yielded final concentrations for eachmicrobial organism estimated to be 5×10⁵ CFU/mL (verified by colonyquantification on appropriate agar plates, data is not presented). Testcompound concentrations ranged from a high-test of 1:2 (100 μg/mL)) to alow test of 1:2048 (0.1 μg/mL) using a two-fold dilution scheme. Theplates were incubated for 24 hours at 37° C., and the microbial growthat each concentration of compound was determined by measuring theoptical density at 625 nm on a Molecular Devices SpectraMax Plus-384plate reader. The MIC for each compound was determined as the lowestcompound dilution that completely inhibited microbial growth.

Antibacterial Assay Results for Staphylococcus aureus Mu50 (ATCC700699), Methicillin-Resistant Staphylococcus aureus (ATCC 43300),Multi-Drug-Resistant Staphylococcus epidermidis (ATCC 700562)

Microsoft Excel 2003 was used to analyze and graph the data, and the MIC(minimal inhibitory concentration) was determined from the resultingdata. The MIC is defined as the lowest concentration of compound thatcompletely inhibited bacterial.

Activity for Compounds was determined in the assays described. Theminimum inhibitory concentration (μg/ml) was determined to be in a givenrange if at least two of three values fell within that range.

-   -   MIC of the compound in the range of less than 0.98 (μg/ml) is        designated in the table by ++++    -   MIC of the compound in the range of greater than or equal to        0.99 (μg/ml) and less than or equal to 15.6 (μg/ml) is        designated in the table by +++    -   MIC of the compound in the range of greater than or equal to        15.7 (μg/ml) and less than or equal 62.5 (μg/ml) is designated        in the table by ++

MIC of the compound in the range of greater than or equal to 62.6(μg/ml) is designated in the table by +

Methicillin- Staphylococcus Resistant Multi-Drug-Resistant aureusStaphylococcus Staphylococcus Mu50 aureus epidermidis (ATCC Compound(ATCC 700699) (ATCC 43300) 700562) 1 +++ +++ +++ 12 +++ +++ +++ 15 ++++++ +++ 16 +++ +++ +++ 17 +++ +++ +++ 21 +++ +++ +++ 30 +++ +++ +++ 31++ +++ +++

Example 2 Preparation and Biological Activity of Further CompoundsAccording to the Present Invention

General Notes

Melting point determinations were carried out on a Gallenkamp meltingpoint apparatus. Chemical ionization (CI) and electron impact (EI) massspectra were obtained on a Shimadzu QP-5000 mass spectrometer by adirect insertion technique with an electron beam energy of 70 eV.Electrospray (ES) mass spectra were obtained on a VG Autospecspectrometer. High-resolution mass spectra (HRMS) were determined on amicromass QTof2 spectrometer using polyethylene glycol or polypropyleneglycol as the internal standard. The m/z values are stated with theirpeak intensity as a percentage in parentheses. Optical rotations weremeasured using a Jasco polarimeter with a 10 mm path length. Proton andcarbon nuclear magnetic resonance (NMR) spectra were obtained asspecified on a Varian Mercury 300 MHz or Varian Inova 500 MHzspectrometer. Spectra were recorded in the specified deuterated solvent,and referenced to the residual non-deuterated solvent signal. Chemicalshifts (8) in ppm were measured relative to the internal standard. Wheresamples exhibited (E) and (Z) isomers the chemical shifts are separatedby (/). In general, the two forms could not be separated by flashchromatography. Multiplet (m) signals are reported from the centre ofthe peak. Proton and carbon assignments were determined through theinterpretation of two dimensional spectra (COSY, gHSQC and gHMBC).Analytical thin layer chromatography (TLC) was carried out on Mercksilica gel 60 F₂₅₄ pre-coated aluminium plates with a thickness of 0.2mm. All column chromatography was performed under ‘flash’ conditions onMerck silica gel 60 (230-400 mesh). Chromatography solvent mixtures weremeasured by volume. Organic solvent extracts were dried with anhydrousmagnesium sulfate, and the solvent removed under reduced pressure with aBuchi rotary evaporator. Solvents were purified and dried based uponstandard techniques.¹²⁰ All compounds were judged to be of greater than95% purity based upon ¹H NMR and TLC analysis. Starting materials andreagents were purchased from Sigma-Aldrich Pty Ltd or Auspep Pty Ltd andwere used as received. The Grubbs' first generation catalyst used wasspecifically benzylidene bis(tricyclohexylphosphene)dichlororuthenium.

Proton and carbon NMR spectra for all compounds were assigned using thenumbering systems illustrated below. Cyclic peptoids were named usingthe IUPAC “superatom” convention, in which the aromatic ring isconsidered equivalent to, and sequentially numbered like all other atomsin the macrocycle.¹²¹

General Synthetic ProceduresN-Boc and Pmc Deprotection (Procedure A)

The N-Boc or Pmc protected amine was stirred for 3 h in 1:1 DCM/TFA (10mL) solution at RT. The solvent was removed under reduced pressure, andthe residue was resuspended in a minimal volume of methanol. Thesolution was then treated with an excess of 1M HCl/ether solution andthe solvent evaporated. The crude product was purified by precipitationfrom DCM and/or MeOH by addition of diethyl ether.

Peptide Coupling (Procedure B)

To a solution of the acid (1 equiv.) in DMF or CH₃CN (10 mL) at roomtemperature was added HOBt (1.1 equiv.), EDCI (1 equiv.) and the amine(1.2 equiv.). If the amine was a hydrochloride salt, DIPEA (1 equiv.)was also added. The mixture was allowed to stir for 16 h before dilutionwith EtOAc (30 mL) and washing with water (30 mL) and brine (30 mL). Theorganic fraction was dried (MgSO₄) and further purified by columnchromatography if required.

N-Fmoc Deprotection (Procedure C)

The Fmoc protected amine was stirred in 1% piperidine/acetonitrile (10mL) for 3 h at RT. The solvent was removed under reduced pressure andthe crude product was purified by flash column chromatography (15:1,DCM/MeOH) to yield the free amine.

Macrocyclization by Olefin Metathesis (Procedure D)

To a solution of the precursor tripeptide (1 equiv.) in DCM (to 0.004 M)was added Grubbs' first generation catalyst (15 mol %) and the resultingsolution was heated at reflux for 48 h before the solvent was removed byevaporation and the product isolated by flash column chromatography(15:1, DCM/MeOH) to yield the corresponding macrocycle.

EXPERIMENTAL Ethyl(2S)-2-acetamido-3-(4-allyloxyphenyl)propanoate (15)

To a solution of ethyl(2S)-2-acetamido-3-(4-hydroxyphenyl) propanoatemonohydrate 13 (2.69 g, 9.98 mmol) and anhydrous K₂CO₃ (2.75 g, 20.0mmol) in DMF (15 mL) was added allyl bromide (2.42 g, 19.96 mmol). Theresulting mixture was allowed to stir for 16 h under nitrogen before thereaction was quenched with water (30 mL) and extracted with ethylacetate (3×50 mL). The combined organic fractions were washed with water(5×50 mL), dried and the solvent was evaporated to yield the titlecompound (2.91 g, 9.98 mmol, 100%) as a white solid, which had spectraldata in agreement with that reported.¹²² [α]_(D) ²⁵+23.1 (c. 0.1, EtOH).Mp 69-70° C. (lit. 69.5° C.)¹²² ¹H NMR (CDCl₃, 300 MHz): δ 7.02 (d,J=8.4 Hz, 2H, ArH2′ and ArH6′); 6.83 (d, J=8.8 Hz, 2H, ArH3′ and ArH5′);6.14 (d, J=8.0 Hz, 1H, NH); 6.06 (m, 1H, H2″); 5.31 (m, 2H, H3″); 4.81(dd, J=13.5, 6.0 Hz, 1H, H2); 4.50 (d, J=5.1 Hz, 2H, H1″); 4.16 (dd,J=13.9, 6.7 Hz, 2H, OCH ₂CH₃); 3.04 (m, 2H, H3); 1.98 (s, 3H, NCOCH₃);1.25 (t, J=7.2 Hz, 3H, OCH₂CH ₃). Mass Spectrum (CI, +ve) m/z 292 (100%)[MH⁺]. HRMS calcd for C₁₆H₂₂NO₄ 292.1549, found 292.1559.

(2S)-2-Acetamido-3-(4-allyloxyphenyl)propanoic acid (16)

To a solution of 15 (2.90 g, 9.98 mmol) in THF/water, (3:1, 80 mL) wasadded lithium hydroxide monohydrate (838 mg, 20.0 mmol) and theresulting suspension was allowed to stir for 16 h. The reaction mixturewas diluted with water (30 mL) and the THF was removed by evaporation.The aqueous layer was extracted with DCM (40 mL) to remove unreactedstarting material. The aqueous phase was acidified with 10% HCl and theresulting precipitate was extracted with DCM (3×40 mL). The combinedorganic fractions were dried and evaporated to yield the title compound(2.62 g, 9.98 mmol, 100%) as white needles, which had spectral data inagreement with that reported.¹²² Mp 170-172° C. (lit. 200° C.)¹²² ¹H NMR(D₆ acetone, 300 MHz): δ 7.09 (s, 1H, NH); 7.04 (d, J=8.4 Hz, 2H, ArH2′and ArH6′); 6.73 (d, J=8.4 Hz, 2H, ArH3′ and ArH5′); 5.94 (m, 1H, H2″);5.27 (dd J=1.3 Hz, 17.3 Hz, 1H, H3_(a)″); 5.10 (dd J=1.3, 10.5 Hz, 1H,H3b″); 4.52 (m, 1H, H2); 4.41 (d J=5.5 Hz, 2H, H1″); 2.98 (dd, J=5.7,14.1 Hz, 2H, H3_(a)); 2.79 (dd, J=8.1, 14.1 Hz, 2H, H3b); 1.75 (s, 3H,NCOCH ₃). Mass Spectrum (CI, +ve) m/z 264 (100%) [MH⁺]. HRMS calcd forC₁₄H₁₈NO₄ 264.1236, found 264.1246.

Methyl(2S)-2-amino-4-pentenoate hydrochloride (18)

To a suspension of (2S)-2-amino-4-pentanoic acid 17 (200 mg, 1.74 mmol)in MeOH (6 mL) at 0° C. was added dropwise thionyl chloride (1 mL). Theresulting solution was allowed to stir for 16 h before the solvent wasremoved by evaporation and the product crystallized with ether. Theether was removed by evaporation to yield the title compound (287 mg,1.74 mmol, 100%) as a white solid, which had spectral data in agreementwith that reported.⁸² Mp 172-174° C. (lit. 174-176° C.)⁸² ¹H NMR (CDCl₃,300 MHz): δ 8.74 (bs, 3H, NH₃ ⁺); 5.88 (m, 1H, H4); 5.32 (d, J=16.8 Hz,1H, H15_(a)); 5.25 (d, J=10.2 Hz, 1H, H5_(b)); 4.29 (t, J=5.1 Hz, 1H,H2); 3.81 (s, 3H, OCH₃); 2.86 (t, J=5.7 Hz, 2H, H3). Mass Spectrum (ES,+ve) m/z 130 (100%) [M+]. HRMS calcd for C₆H₁₂NO₂ 130.0868, found130.0876.

Methyl(2S,5R)-2-allyl-3-aza-9-(tert-butoxycarboxamido)-5-(9H-9-fluorenylmethyloxycarboxamido)-4-oxononanoate(19)

The title compound was synthesised using the general peptide couplingprocedure (Procedure B), from 18 (186 mg, 1.62 mmol) and(2R)-6-tert-butoxycarboxamido-2-(9H-9-fluorenylmethyloxycarboxamido)hexanoic acid (633 mg, 1.35 mmol) to afford 19 (733 mg, 1.27mmol, 94%) as a cream solid. Mp 117-120° C. ¹H NMR (CDCl₃, 300 MHz): δ7.76 (d, J=7.6 Hz, 2H, ArH1″ and ArH8″); 7.59 (d, J=7.6 Hz, 2H, ArH4″and ArH5″); 7.39 (t, J=7.6 Hz, 2H, ArH3″ and ArH6″); 7.31 (dd, J=9.0,7.2, 1.2 Hz, 2H, ArH2″ and ArH7″); 6.75 (d, J=7.2 Hz, 1H, NH); 5.65 (m,1H, H2′); 5.07 (m, 2H, H3′); 4.65 (m, 2H, H2 and NH); 4.38 (d, J=6.7 Hz,2H, OCH ₂—H9″); 4.21 (m, 2H, H15 and H9″); 3.71 (s, 3H, OCH₃); 3.10 (d,J=6.3 Hz, 2H, H9); 2.52 (m, 2H, H1′); 1.85 (m, 2H, H8); 1.66 (m, 2H,H7); 1.39 (m 2H, H7); 1.43 (s, 9H, C(CH₃)₃). Mass Spectrum (ES, +ve) m/z579.9 (80%) [M], 479.9 (100%) [MH⁺ (less Boc)]. HRMS calcd forC₃₂H₄₂N₃O₇ 580.3023, found 580.3041.

Methyl(2S,5R)-2-allyl-5-amino-3-aza-9-(tert-butoxycarboxamido)-4-oxononanoate(20)

The title compound was synthesized using the general N-Fmoc deprotectionprocedure (Procedure C), from 19 (715 mg, 1.23 mmol) to yield 20 (436mg, 1.22 mmole, 99%) as a cream oil, and is in agreement with theliterature.⁷⁸ ¹H NMR (CDCl₃, 300 MHz): δ 7.75 (d, J=8.0 Hz, 1H, NH);5.70 (m, 1H, H2′); 5.13 (m, 2H, H3′); 4.80 (bs, 1H, NH); 4.64 (m, 1H,H2); 3.74 (s, 3H, OCH₃); 3.38 (dd, J=4.6, 7.6 Hz, 1H, H5); 3.12 (d,J=6.3 Hz, 2H, H9); 2.57 (m, 2H, H1′); 1.61 (m, 8H, H6, H7, H8 and NH₂);1.44 (s, 9H, C(CH₃)₃). Mass Spectrum (ES, +ve) m/z 358.5 (70%) [MH⁺],258.4 (100%) [MH⁺ (less Boc)]. HRMS calcd for C₁₇H₃₂N₃O₅ 358.2342, found358.2334.

Methyl(2S,5R,8S)-2-allyl-8-(4-allyloxybenzyl)-3,6,9-triaza-5-(4-[tert-butoxycarboxamido]butyl)-4,7,10-trioxoundecanoate(21)

The title compound was synthesised using the general peptide couplingprocedure (Procedure B), from 20 (440 mg, 1.20 mmol) and 16 (270 mg,1.03 mmol) to afford 21 (424 mg, 0.70 mmol, 69%) as a white solid. Mp149-150° C. ¹H NMR (CDCl₃, 300 MHz): δ 7.20 (d, J=8.0 Hz, 1H, NH); 7.11(d, J=8.4 Hz, 2H, ArH2′″ and ArH6′″); 6.84 (d, J=8.4 Hz, 2H, ArH3′″ andArH5′″); 6.67 (d, J=8.0 Hz, 1H, NH); 6.48 (d, J=7.2 Hz, 1H, NH); 6.04(m, 1H, H2″″); 5.67 (m, 1H, H2′); 5.41 (dd, J=1.3, 17.3 Hz, 1H,H3_(a)″″); 5.28 (dd, J=1.3, 10.5 Hz, 1H, H3_(b)″″); 5.10 (m, 2H, H3′);4.75 (t, J=5.9 Hz, 1H, H2); 4.60 (m, 1H, H8); 4.50 (d, J=5.5 Hz, 2H,H1″″); 4.42 (dd, J=7.6, 13.1 Hz, 1H, H5); 3.71 (s, 3H, OCH₃); 2.97 (m,4H, H4″ and ArCH₂); 2.52 (m, 2H, H1′); 1.97 (s, 3H, H11); 1.44 (s, 9H,C(CH₃)₃); 1.34 (m, 6H, H1″, H2″ and H3″). Mass Spectrum (ES, +ve) m/z603.4 (40%) [MH⁺], 503.4 (100%) [MH⁺ (less Boc)]. HRMS calcd forC₃₁H₄₇N₄O₈ 603.3394, found 603.3389.

(7S,10R,13S,4E/Z)-13-Acetamido-8,11-diaza-10-(4-[tert-butoxycarboxamido]butyl)-7-methoxycarbonyl-2-oxa-9,12-dioxo-1(1,4)phenylenacyclotetradecaphane-4-ene(22)

The title compound was prepared using the general procedure for olefinmetathesis (Procedure D), from 21 (277 mg, 0.46 mmol) to yield 22 (199mg, 0.35 mmol, 75%) as a brown solid. Mp 178-180° C. ¹H NMR (CDCl₃, 300MHz): δ 8.08 (m, 2H, NH); 7.07 (m, 2H, ArH); 6.71 (m, 2H, ArH); 5.63 (m,2H, H4 and H5); 4.48 (m, 4H, H7, H13 and H3); 4.13 (m, 2H, NH and H10);3.60 (m, 3H, OCH₃); 2.79 (bs, 4H, H4′ and H14); 2.38 (m, 2H, H6); 1.80(m, 3H, NCOCH₃); 1.10 (m, 6H, H1′, H2′ and H3′); 1.26 (s, 9H, C(CH₃)₃).Mass Spectrum (ES, +ve) m/z 575.3 (20%) [MH⁺], 475.3 (100%) [MH⁺ (lessBoc)]. HRMS calcd for C₂₉H₄₃N₄O₈ 575.3081, found 575.3091.

(7S,10R,13S,4E/Z)-13-Acetamido-10-(4-aminobutyl)-8,11-diaza-7-methoxycarbonyl-2-oxa-9,12-dioxo-1(1,4)phenylenacyclotetradecaphane-4-enehydrochloride (12)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 22 (49 mg, 0.084 mmol) to yield 12 (17 mg,0.033 mmol, 49%) as a highly hydroscopic yellow solid. ¹H NMR (CD₃OD,300 MHz): δ 7.10 (m, 3H, ArH and NH); 6.85 (bs, 1H, NH); 6.71 (d, J=7.5Hz, 2H, ArH); 5.75 (m, 2H, H4 and H5); 4.39 (m, 5H, H3, H7, H₁₀ andH13); 3.68 (s, 3H, OCH₃); 2.85 (m, 4H, H6 and H4′); 2.52 (m, 2H, H14);1.93 (s, 3H, NCOCH₃); 1.50 (m, 6H, H1′, H2′ and H3′). ¹³C NMR (CD₃OD, 75MHz): δ 173.5, C9; 173.1, 7-CO; 173.0, 13-NCO; 172.6, C12; 157.7,1-ArC1; 132.4, 1-ArCH2 and 1-ArCH6; 131.1, C4; 129.6, C5; 129.3, 1-ArC4;116.8, 1-ArCH3 and 1-ArCH5; 70.0, C3; 57.9, C13; 54.9, C10; 53.5, C4′;53.0, OCH₃; 40.7, C7; 38.2, C14; 32.1, C1′; 31.7, C6; 28.0, C3′; 23.5,NCOCH₃; 22.6, C2′. Mass Spectrum (ES, +ve) m/z 475.3 (100%) [M⁺]. HRMScalcd for C₂₄H₃₅N₄O₆ 475.2557, found 475.2534.

Methyl(2S,5S)-2-allyl-3-aza-9-(tert-butoxycarboxamido)-5-(9H-9-fluorenylmethyloxycarboxamido)-4-oxononanoate(23)

To a solution of 18 (430 mg, 2.61 mmol) and(2S)-6-tert-butoxycarboxamido-2-(9H-9-fluorenylmethyloxy)carboxamidohexanoic acid (1.22 g, 2.61 mmol) in DCM (10 mL) was added EDCI (500 mg,2.61 mmol) and a catalytic quantity of DMAP. The resulting mixture wasallowed to stir at RT for 16 h. The reaction was diluted with DCM (25mL), then the organic layer was washed with brine (2×25 mL) and water(2×25 mL) and dried, before being concentrated. The crude product waspurified by flash column chromatography (25:1 DCM/MeOH) to afford thetitle compound (1.31 g, 2.27 mmol, 87%) as a cream coloured solid. Mp123-126° C. ¹H NMR (CDCl₃, 300 MHz): δ 7.76 (d, J=7.6 Hz, 2H, ArH1″ andArH8″); 7.59 (d, J=7.6 Hz, 2H, ArH4″ and ArH5″); 7.40 (t, J=7.6 Hz, 2H,ArH3″ and ArH6″); 7.31 (ddd, J=9.0, 7.2, 1.2 Hz, 2H, ArH2″ and ArH7″);6.46 (bs, 1H, NH); 5.64 (m, 1H, H2′); 5.44 (s, 1H, NH); 5.10 (m, 2H,H3′); 4.65 (m, 1H, H2); 4.39 (d, J=7.2 Hz, 2H, OCH ₂—H9″); 4.22 (m, 1H,H5); 4.17 (bs, 1H, H9″); 3.74 (s, 3H, OCH₃); 3.11 (m, 2H, H9); 2.55 (m,2H, H1′); 1.85 (m, 2H, H7); 1.65 (m, 2H, H6); 1.50 (m 2H, H8); 1.44 (s,9H, C(CH₃)₃). Mass Spectrum (ES, +ve) m/z 580.5 (10%) [MH⁺], 130.5(100%) [MH⁺ (less allylgly)]. HRMS calcd for C₃₂H₄₂N₃O₇ 580.3023, found580.3025.

Methyl(2S,5S)-2-allyl-5-amino-3-aza-9-(tert-butoxycarboxamido)-4-oxononanoate(24)

The title compound was synthesized using the general N-Fmoc deprotectionprocedure (Procedure C), from 23 (1.27 g, 2.19 mmol) to yield 24 (778mg, 2.18 mmole, 100%) as a cream oil. ¹H NMR (CDCl₃, 300 MHz): δ 7.81(d, J=8.0 Hz, 1H, NH); 5.69 (m, 1H, H2′); 5.11 (m, 2H, H3′); 4.76 (bs,1H, NH); 4.67 (m, 1H, H2); 3.75 (s, 3H, OCH₃); 3.39 (dd, J=4.6, 7.6 Hz,1H, H5); 3.12 (d, J=6.3 Hz, 2H, H9); 2.54 (m, 2H, H1′); 1.52 (m, 8H, H6,H7, H8 and NH₂); 1.44 (s, 9H, C(CH₃)₃). ¹³C NMR (CDCl₃, 75 MHz): δ174.8, C4; 172.1, C1; 156.0, NCO₂; 132.2, C2′; 118.9, C3′; 78.9,C(CH₃)₃; 54.8, C5; 52.2, C2; 51.1, OCH₃; 40.0, C9; 36.4, C1′; 34.4, C6;29.7, C8; 28.3, C(CH₃)₃; 22.6, C7. Mass Spectrum (ES, +ve) m/z 358.5(85%) [MH⁺], 258.4 (100%) [MH⁺ (less Boc)]. HRMS calcd for C₁₇H₃₂N₃O₅358.2342, found 358.2339.

Methyl(2S,5S,8S)-2-allyl-8-(4-allyloxybenzyl)-3,6,9-triaza-5-(4-[tert-butoxycarboxamido]butyl)-4,7,10-trioxoundecanoate(25)

To a solution of 24 (782 mg, 2.19 mmol) and 16 (576 mg, 2.19 mmol) inDCM (10 mL) was added EDCI (420 mg, 2.19 mmol) and a catalytic quantityof DMAP. The resulting mixture was allowed to stir at RT for 16 h. Thereaction was diluted with DCM (25 mL) and the organic layer was washedwith brine (2×25 mL) and water (2×25 mL) and dried, before beingconcentrated by evaporation. The crude product was purified by flashcolumn chromatography (25:1 DCM/MeOH) to afford the title compound (664mg, 1.10 mmol, 50%) as a 1:1 mixture of 2 epimers, as a white solid. Mp112-114° C. ¹H NMR (CDCl₃, 300 MHz): δ 7.09 (m, 2H, ArH2′″ and ArH6′″);6.91 (d, J=8 Hz, 1H, NH); 6.82 (m, 2H, ArH3′″ and ArH5′″); 6.69 (d,J=8.0 Hz, 1H, NH); 6.55 (bs, 1H, NH); 6.03 (m, 1H, H1″″); 5.68 (m, 1H,H2′); 5.25 (m, 4H, H3′ and H3″″); 4.96 (bs, 1H, H2); 4.86 (bs, 1H, H8);4.67 (m, 2H, H2″″); 4.48 (dd, J=3.0, 8.4 Hz, 1H, H5); 3.74/3.71 (s, 3H,OCH₃); 3.04 (m, 4H, H4″ and ArCH₂); 2.51 (m, 2H, H1′); 1.98/1.96 (s, 3H,H11); 1.79 (s, 2H, H2″); 1.60 (s, 2H, H1″); 1.43 (s, 9H, C(CH₃)₃); 1.28(s, 2H, H3″). Mass Spectrum (ES, +ve) m/z 603.4 (35%) [MH⁺], 503.4(100%) [MH⁺ (less Boc)]. HRMS calcd for C₃₁H₄₇N₄O₈ 603.3394, found603.3397.

(7S,10S,13S,4E/Z)-13-Acetamido-8,11-diaza-10-(4-[tert-butoxycarboxamido]butyl)-7-methoxycarbonyl-2-oxa-9,12-dioxo-1(1,4)phenylenacyclotetradecaphane-4-ene(26)

The title compound was prepared using the general procedure for olefinmetathesis (Procedure D) using 25 (311 mg, 0.52 mmol) to yield 26 as amixture of epimers and E/Z isomers (228 mg, 0.40 mmol, 76%) as a brownsolid. Mp 196-201° C. ¹H NMR (CDCl₃, 300 MH⁺): δ 7.54 (m, 2H, NH); 7.34(bs, 1H, NH); 7.06 (m, 2H, ArH); 6.81/6.73 (d, J=8.0 Hz, 2H, ArH); 5.66(d, J=16.4 Hz, 1H, H4-trans); 5.55 (m, 1H, H5); 4.90 (m, 2H, H7 andH13); 4.64 (m, 3H, H2 and H10); 3.80/3.77 (s, 3H, OCH₃); 3.10 (m, 4H, H6and H4′); 2.70 (m, 2H, H14); 2.10 (s, 3H, NCOCH ₃); 1.51 (m, 6H, H1′,H2′ and H3′); 1.44/1.40 (s, 9H, C(CH₃)₃). Mass Spectrum (ES, +ve) m/z575.3 (25%) [MH⁺], 475.3 (40%) [MH⁺ (less Boc)]. HRMS calcd forC₂₉H₁₃N₄O₈ 575.3081, found 575.3092.

(7S,10S,13S,4E/Z)-13-Acetamido-10-(4-aminobutyl)-8,11-diaza-7-methoxycarbonyl-2-oxa-9,12-dioxo-1(1,4)phenylenacyclotetradecaphane-4-enehydrochloride (27)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A) using 26 (220 mg, 0.380 mmol) to yield 27 as amixture of epimers and E/Z isomers (152 mg, 0.300 mmol, 79%) as a highlyhydroscopic yellow solid. ¹H NMR (CD₃OD, 300 MHz): δ 8.19 (d, J=8.4 Hz,1H, NH); 6.98/6.92 (d, J=8.0 Hz, 2H, ArH); 6.74/6.64 (d, J=8.0 Hz, 2H,ArH); 5.57 (d, J=16.0 Hz, 2H, H4-trans); 5.39 (m, 1H, H5); 4.53 (m, 4H,H7, H13 and H2); 4.21 (m, 1H, H10); 3.93 (bs, 1H, NH); 3.63/3.60 (s, 3H,OCH₃); 2.76 (m, 6H, H6, H4′ and H14); 1.99/1.89 (s, 3H, NCOCH ₃); 1.64(m, 2H, H2′); 1.51 (bs, 2H, H3′); 1.22 (m, 2H, H1′). ¹³C NMR (CD₃OD, 75MHz): δ 174.5, C9; 173.3, 7-CO; 173.1, 13-NCO; 172.5, C12; 157.7,1-ArC1; 131.4, 1-ArCH2 and 1-ArCH6; 131.1, C4; 129.5, C5; 129.1, 1-ArC4;116.4, 1-ArCH3 and 1-ArCH5; 66.9, C3; 57.7, C13; 53.9, C10; 53.1, C4′;53.0, OCH₃; 40.5, C7; 38.1, C14; 32.0, C1′; 31.8, C6; 28.0, C3′; 23.5,NCOCH₃; 22.5, C2′. Mass Spectrum (ES, +ve) m/z 475.4 (100%) [M⁺]. HRMScalcd for C₂₄H₃₅N₄O₆ 475.2557, found 475.2581.

Methyl(2S,5R)-2-allyl-3-aza-5-(9H-9-fluorenylmethyloxycarboxamido)-8-[(2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl)guanidino]-4-oxooctanoate(28)

The title compound was synthesised using the general peptide couplingprocedure (Procedure B), from 18 (287 mg, 1.74 mmol) and(2R)-2-(9H-9-fluorenylmethyloxycarboxamido)-8-[(2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl)guanidino]pentanoicacid (961 mg, 1.45 mmol) to afford 28 (1.01 g, 1.31 mmol, 90%) as abrown solid. Mp 96-100° C. ¹H NMR (CDCl₃, 300 MHz): δ 7.70 (d, J=7.5 Hz,2H, ArH1″ and ArH8″); 7.52 (d, J=7.2 Hz, 2H, ArH4″ and ArH5″); 7.35 (bs,1H, NH); 7.33 (dd, J=7.2, 7.2 Hz, 2H, ArH3″ and ArH6″); 7.20 (t, J=7.2Hz, 2H, ArH2″ and ArH7″); 6.35 (s, 2H, NH); 6.26 (bs, 2H, NH); 5.62 (m,1H, H2′); 5.03 (d, J=18.0 Hz, 1H, H3_(a)′); 4.98 (d, J=10.2 Hz, 1H,H3_(b)′); 4.53 (dd, J=7.2, 12.9 Hz, 1H, H2); 4.27 (d, J=6.6 Hz, 2H, OCH₂—H9″); 4.10 (m, 2H, H5 and H9″); 3.63 (s, 3H, OCH₃); 3.23 (m, 2H, H8);2.57 (s, 3H, 7′″-CH₃); 2.54 (s, 3H, 5′″-CH₃); 2.49 (m, 4H, H1′ andH4′″); 2.06 (s, 3H, 8′″-CH₃); 1.88 (m, 2H, H7); 1.71 (t, J=6.6 Hz, 2H,H3); 1.61 (m, 2H, H6); 1.24 (s, 6H, 2×2′″-CH₃). Mass Spectrum (ES, +ve)m/z 774 (100%) [MH⁺]. HRMS calcd for C₄₁H₅₂N₅O₈S 774.3537, found774.3559.

Methyl(2S,5R)-2-allyl-5-amino-3-aza-8-[(2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl)guanidino]-4-oxooctanoate(29)

The title compound was synthesized using the general N-Fmoc deprotectionprocedure (Procedure C), from 28 (717 mg, 0.93 mmol) to yield 29 (407mg, 0.74 mmol, 80%) as a cream oil, and is in agreement with theliterature.⁸⁰ ¹H NMR (CDCl₃, 300 MHz): δ 7.87 (d, J=8.1 Hz, 1H, NH);6.36 (bs, 3H, NH); 5.68 (m, 1H, H2′); 5.10 (m, 2H, H3′); 4.52 (dd,J=6.9, 12.9 Hz, 1H, H2); 3.71 (s, 3H, OCH₃); 3.42 (m 1H, H5); 3.19 (dd,J=6.9, 11.1 Hz, 2H, H8); 2.62 (t, J=6.9 Hz, 2H, H4″); 2.56 (s, 3H,7″-CH₃); 2.54 (s, 3H, 5″-CH₃); 2.49 (m, 2H, H1′); 2.10 (s, 3H, 8″-CH₃);1.80 (t, J=6.9 Hz, 2H, H2″); 1.74 (m, 2H, H7); 1.58 (m, 2H, H6); 1.30(s, 6H, 2×2″-CH₃). Mass Spectrum (ES, +ve) m/z 552 (100%) [MH⁺]. HRMScalcd for C₂₆H₄₂N₅O₆S 552.2856, found 552.2839.

Methyl(2S,5R,8S)-2-allyl-8-(4-allyloxybenzyl)-3,6,9-triaza-5-([{2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl}guanidino]propyl)-4,7,10-trioxoundecanoate(30)

The title compound was synthesised using the general peptide couplingprocedure (Procedure B) using 29 (387 mg, 0.70 mmol) and 16 (153 mg,0.58 mmol) to afford 30 (336 mg, 0.42 mmol, 73%) as a light brown solid.Mp 172-176° C. ¹H NMR (CDCl₃, 500 MHz): δ 7.75 (d, J=7.5 Hz, 1H, NH);7.11 (d, J=8.7 Hz, 2H, ArH2″″ and ArH6″″); 6.78 (d, J=8.4 Hz, 2H, ArH3″″and ArH5″″); 6.36 (bs, 2H, NH); 6.18 (bs, 1H, NH); 5.98 (m, 1H, H2′″″);5.69 (m, 1H, H2′); 5.36 (dd, J=1.5, 17.4 Hz, 1H, H3_(a)′″″); 5.24 (dd,J=1.5, 10.5 Hz, 1H, H3_(b)′″″); 5.08 (d, J=15.6 Hz, 1H, H3_(a)′); 5.04(d, J=8.4 Hz, 1H, H3_(b)′); 4.48 (m, 2H, H12 and H5); 4.42 (d, J=4.8 Hz,1H, H1′″″); 4.29 (m, 1H, H8); 3.69 (s, 3H, OCH₃); 3.05 (m, 2H, H3″);2.99 (m, 2H, ArCH₂); 2.63 (t, J=6.9 Hz, 2H, H14′″); 2.59 (s, 3H,7′″-CH₃); 2.57 (s, 3H, 5′″-CH₃); 2.54 (m, 2H, H11′); 2.09 (s, 3H,8′″-CH₃); 1.93 (s, 3H, H11); 1.80 (t, J=6.6 Hz, 2H, H3′″); 1.51 (m, 4H,H1″ and H2″); 1.30 (s, 6H, 2×2′″-CH₃). Mass Spectrum (ES, +ve) m/z 797(100%) [MH⁺]. HRMS calcd for C₄₀H₅₇N₆O₉S 797.3908, found 797.3913.

(7S,10R,13S,4E/Z)-13-Acetamido-8,11-diaza-10-(3[{2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl}guanidino]propyl)-7-methoxycarbonyl-2-oxa-9,12-dioxo-1(1,4)phenylenacyclotetradecaphane-4-ene(31)

The title compound was prepared using the general procedure for olefinmetathesis (Procedure D), from 30 (104 mg, 0.13 mmol) to yield 31 (103mg, 0.13 mmol, 100%) as a grey solid. Mp 172-175° C. ¹H NMR (CDCl₃, 300MHz): δ 7.04 (m, 2H, ArH); 6.72 (m, 2H, ArH); 6.37 (bs, 1H, NH); 5.45(m, H4 and H5); 4.79 (m, 2H, H3); 4.57 (m, 3H, H7, H10 and H13); 3.63(s, 3H, OCH₃); 2.97 (m, 4H, H3′ and H6); 2.54 (m, 10H, H14, 7″-CH₃,5″-CH₃ and H4″); 2.06 (s, 3H, 8″-CH₃); 1.90 (s, 3H, NCOCH ₃); 1.76 (m,2H, H1′); 1.48 (m, 2H, H3″); 1.27 (s, 6H, 2×2″-CH₃). Mass Spectrum (ES,−ve) m/z 767 (100%) [MH⁺]. HRMS calcd for C₃₈H₅₃N₆O₉S 769.3595, found769.3558.

(7S,10R,13S,4E/Z)-13-Acetamido-8,11-diaza-10-(3-[guanidino]propyl)-7-methoxycarbonyl-2-oxa-9,12-dioxo-1(1,4)phenylenacyclotetradecaphane-4-ene(32)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 31 (60 mg, 0.078 mmol) to yield 32 (38 mg,0.071 mmol, 91%) as a white solid. Mp 218-224° C. ¹H NMR (CD₃OD, 300MHz): δ 7.10 (m, 2H, ArH); 6.79 (m, 2H, ArH); 5.70 (m, 1H, H5); 5.51 (m,1H, H4); 4.44 (m, 5H, H3, H7, H10 and H13); 3.69 (m, 3H, OCH₃); 3.10 (m,2H, H3′); 2.94 (m, 2H, H14); 2.49 (m, 2H, H6); 1.94 (s, 3H, NCOCH ₃);1.71 (m, 2H, H1′); 1.33 (m, 2H, H2′). ¹³C NMR (CD₃OD, 75 MHz): δ 173.6,COOCH₃; 173.5, C11; 173.1, C9; 172.4, NCOCH₃; 158.4, CN₃; 157.4, 1-ArC4;131.5, C4; 129.5, C5; 129.1, 1-ArCH2 and 1-ArCH6; 129.0, 1-ArC1; 116.5,1-ArCH3 and 1-ArCH5; 66.9, C3; 57.5, C7; 56.2, C10; 54.3, C10; 53.6,C3′; 52.5, OCH₃; 42.1, C6; 38.7, C14; 35.3, NCOCH₃; 26.6, C1′; 22.7,C2′. Mass Spectrum (ES, +ve) m/z 503 (100%) [M⁺]. HRMS calcd forC₂₄H₃₅N₆O₆ 503.2618, found 503.2626.

Methyl(2S,5S)-2-allyl-3-aza-5-(9H-9-fluorenylmethyloxycarboxamido)-8-[(2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl)guanidino]-4-oxooctanoate(33)

The title compound was synthesised using the general peptide couplingprocedure (Procedure B), from 18 (287 mg, 1.74 mmol) and(2S)-2-(9H-9-fluorenylmethyloxycarboxamido)-8-[(2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl)guanidino]pentanoicacid (961 mg, 1.45 mmol) to afford 33 (936 mg, 1.21 mmol, 83%) as abrown solid. Mp 90-94° C. ¹H NMR (CDCl₃, 300 MHz): δ 7.71 (d, J=7.5 Hz,2H, ArH1″ and ArH8″); 7.54 (d, J=7.0 Hz, 2H, ArH4″ and ArH5″); 7.39 (bs,1H, NH) 7.34 (t, J=7.5 Hz, 2H, ArH3″ and ArH6″); 7.22 (t, J=7.5 Hz, 2H,ArH2″ and ArH7″); 6.34 (bs, 1H, NH); 6.12 (d, J=7.5 Hz 1H, NH); 5.65 (m,1H, H2′); 5.03 (d, J=17.0 Hz, 1H, H3_(a)′); 4.98 (d, J=10.0 Hz, 1H,H3_(b)′); 4.54 (m, 1H, H2); 4.36 (m, 1H, H5); 4.29 (d, J=7.2 Hz, 2H, OCH₂—H9″); 4.11 (m, 1H, H9″); 3.65 (s, 3H, OCH₃); 3.25 (m, 2H, H8); 2.58(s, 3H, 7′″-CH₃); 2.55 (s, 3H, 5′″-CH₃); 2.48 (m, 4H, H1′ and H4′″);2.07 (s, 3H, 8′″-CH₃); 1.93 (m, 2H, H6); 1.73 (t, J=6.5 Hz, 2H, H3′″);1.60 (m, 2H, H7); 1.26 (s, 6H, 2×2′″-CH₃). Mass Spectrum (ES, +ve) m/z774 (20%) [MH⁺], 130 (100%) [allylGly]. HRMS calcd for C₄₁H₅₂N₅O₈S774.3537, found 774.3517.

Methyl(2S,5S)-2-allyl-5-amino-3-aza-8-[(2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl)guanidino]-4-oxooctanoate(34)

The title compound was synthesized using the general N-Fmoc deprotectionprocedure (Procedure C), from 33 (749 mg, 0.97 mmol) to yield 34 (259mg, 0.47 mmol, 48%) as a cream oil, which had spectral data in agreementwith that reported.⁸⁰ ¹H NMR (CDCl₃, 300 MHz): δ 7.86 (d, J=8.1 Hz, 1H,NH); 6.33 (bs, 3H, NH); 5.66 (m, 1H, H2′); 5.09 (m, 2H, H3′); 4.54 (m,1H, H2); 3.73 (s, 3H, OCH₃); 3.43 (m, 1H, H5); 3.20 (m, 2H, H8); 2.63(t, J=6.9 Hz, 2H, H4″); 2.57 (s, 3H, 7″-CH₃); 2.55 (s, 3H, 5″-CH₃); 2.50(m, 2H, H1′); 2.10 (s, 3H, 8″-CH₃); 1.80 (m, 4H, H7 and H3″); 1.60 (m,2H, H6); 1.30 (s, 6H, 2×2″-CH₃). Mass Spectrum (ES, +ve) m/z 552 (100%)[MH⁺]. HRMS calcd for C₂₆H₄₂N₅O₆S 552.2856, found 552.2856.

Methyl(2S,5S,8S)-2-allyl-8-(4-allyloxybenzyl)-3,6,9-triaza-5-([{2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl}guanidino]propyl)-4,7,10-trioxoundecanoate(35)

The title compound was synthesized using the general peptide couplingprocedure (Procedure B), from 34 (236 mg, 0.43 mmol) and 16 (95 mg, 0.36mmol) to afford 35 (207 mg, 0.25 mmol, 72%) as a light brown solid. Mp99-104° C. ¹H NMR (CDCl₃, 500 MHz): δ 7.77 (d, J=7.8 Hz, 1H, NH); 7.69(bs, 1H, NH); 7.14 (d, J=7.5 Hz, 1H, NH); 7.04 (d, J=8.4 Hz, 2H, ArH2″″and ArH6″″); 6.74 (d, J=8.4 Hz, 2H, ArH3″″ and ArH5″″); 6.41 (bs, 2H,NH); 6.01 (m, 1H, H2′″″); 5.70 (m, 1H, H2′); 5.37 (dd, J=1.5, 17.4 Hz,1H, H3_(a)′″″); 5.25 (dd, J=1.5, 10.5 Hz, ¹H, H3_(b)′″″); 5.07 (d,J=15.3 Hz, 1H, H3_(a)′); 5.03 (d, J=9.3 Hz, 1H, H3_(b)′); 4.74 (m, 1H,H2); 4.64 (bs, 1H, H5); 4.56 (dd, J=6.9, 13.5 Hz, 2H, H8); 4.44 (d,J=5.4 Hz, 2H, H1′″″); 3.68 (s, 3H, OCH₃); 3.17 (d, J=4.5 Hz, 2H, H3″);2.95 (m, 2H, ArCH₂); 2.59 (t, J=6.3 Hz, 2H, H4′″); 2.55 (s, 3H,7′″-CH₃); 2.53 (s, 3H, 5′″-CH₃); 2.50 (m, 2H, H1′); 2.08 (s, 3H,8′″-CH₃); 1.88 (s, 3H, H11); 1.78 (t, J=6.3 Hz, 2H, H13′″); 1.72 (m, 2H,H7); 1.55 (m, 2H, H6); 1.29 (s, 6H, 2×2′″-CH₃). Mass Spectrum (ES, +ve)m/z 797 (100%) [MH⁺]. HRMS calcd for C₄₀H₅₇N₆O₉S 797.3908, found797.3890.

(7S,10S,13S,4E/Z)-13-Acetamido-8,11-diaza-10-(3-[{2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl}guanidino]propyl)-7-methoxycarbonyl-2-oxa-9,12-dioxo-1(1,4)phenylenacyclotetradecaphane-4-ene(36)

The title compound was prepared using the general procedure for olefinmetathesis (Procedure D), from 35 (127 mg, 0.16 mmol) to yield 36 (117mg, 0.15 mmol, 95%) as a grey solid. Mp 224-228° C. ¹H NMR (CDCl₃, 300MHz): δ 6.97 (m, 2H, ArH); 6.71 (m, 2H, ArH); 6.41 (bs, 1H, NH); 5.50(m, H4 and H5); 4.57 (bs, 5H, H3, H7, H10 and H13); 3.67 (s, 3H, OCH₃);3.16 (m, 2H, H3′); 2.56 (m, 10H, H14, 7″-CH₃, 5″-CH₃ and H4″); 2.08 (s,3H, 8″-CH₃); 1.78 (s, 3H, NCOCH ₃); 1.52 (m, 2H, H1′); 1.35 (m, 2H,H3″); 1.30 (s, 6H, 2×2″-CH₃). Mass Spectrum (ES, +ve) m/z 769 (100%)[MH⁺]. HRMS calcd for C₃₈H₅₃N₆O S 769.3595, found 769.3574.

(7S,10S,13S,4E/Z)-13-Acetamido-8,11-diaza-10-(3-[guanidino]propyl)-7-methoxycarbonyl-2-oxa-9,12-dioxo-1(1,4)phenylenacyclotetradecaphane-4-enehydrochloride (37)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 36 (91 mg, 0.12 mmol) to yield 37 as awhite solid (38 mg, 0.071, 59%). Mp 218-220° C. ¹H NMR (CD₃OD, 300 MHz):δ 7.05 (m, 2H, ArH); 6.74 (m, 2H, ArH); 5.80 (m, 1H, H5); 5.55 (m, 1H,H4); 4.51 (m, 5H, H3, H7, H10 and H13); 3.68 (m, 3H, OCH₃); 3.18 (m, 2H,H3′); 2.84 (m, 2H, H14); 2.49 (m, 2H, H6); 1.99 (s, 3H, NCOCH ₃); 1.76(m, 2H, H1′); 1.64 (m, 2H, H2′). ¹³C NMR (CD₃OD, 75 MHz): δ 173.5,COOCH₃; 173.3, C11; 173.2, C9; 172.2, NCOCH₃; 158.9, CN₃; 157.8, 1-ArC4;131.5, C4; 129.9, C5; 129.1, 1-ArCH2 and 1-ArCH6; 129.0, 1-ArC1; 116.2,1-ArCH3 and 1-ArCH5; 66.8, C3; 57.6, C7; 56.0, C10; 54.1, C10; 53.6,C3′; 52.9, OCH₃; 42.0, C6; 38.0, C14; 35.3, NCOCH₃; 26.2, C1′; 22.6,C2′. Mass Spectrum (ES, +ve) m/z 503 (100%) [M⁺]. HRMS calcd forC₂₄H₃₅N₆O₆ 503.2618, found 503.2603.

Methyl(2R)-2-amino-4-pentenoate hydrochloride (38)

To a suspension of (2R)-2-amino-4-pentenoic acid (200 mg, 1.74 mmol) inmethanol (6 mL) at 0° C. was added dropwise thionyl chloride (1 mL). Theresulting solution was allowed to stir for 16 h before the solvent wasremoved by evaporation and the product crystallized with diethyl ether.The diethyl ether was removed by evaporation to yield the title compound(287 mg, 1.74 mmol, 100%) as a white solid which had spectral data inagreement with that reported.¹²³ Mp 135-140° C. ¹H NMR (CDCl₃, 300 MHz):δ 8.70 (bs, 3H, NH₃ ⁺); 5.89 (m, 1H, H4); 5.32 (d, J=17.3 Hz, 1H,H5_(a)); 5.24 (d, J=10.1 Hz, 1H, H5_(b)); 4.31 (m, 1H, H2); 3.81 (s, 3H,OCH₃); 2.87 (t, J=6.3 Hz, 2H, H3). Mass Spectrum (ES, +ve) m/z 130(100%) [M⁺]. HRMS calcd for C₆H₁₂NO₂ 130.0868, found 130.0870.

Methyl(2R,5R)-2-allyl-3-aza-5-(9H-9-fluorenylmethyloxycarboxamido)-8-[(2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl)guanidino]-4-oxooctanoate(39)

The title compound was synthesised using the general peptide couplingprocedure (Procedure B), from 38 (287 mg, 1.74 mmol) and(2R)-2-(9H-9-fluorenylmethyloxycarboxamido)-8-[(2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl)guanidino]pentanoicacid (961 mg, 1.45 mmol) to afford 39 (1.01 g, 1.31 mmol, 90%) as abrown solid. Mp 96-98° C. ¹H NMR (CDCl₃, 500 MHz): δ 7.70 (d, J=7.5 Hz,2H, ArH1″ and ArH8″); 7.53 (d, J=5.0 Hz, 2H, ArH4″ and ArH5″); 7.40 (d,J=4.5 Hz, 1H, NH); 7.34 (t, J=7.5 Hz, 2H, ArH3″ and ArH6″); 7.22 (t,J=7.5 Hz, 2H, ArH2″ and ArH7″); 6.34 (s, 2H, NH); 6.12 (bs, 2H, NH);5.64 (m, 1H, H2′); 5.03 (d, J=17.0 Hz, 1H, H3_(a)′); 4.98 (d, J=10.0 Hz,1H, H3_(b)′); 4.53 (m, 1H, H2); 4.36 (dd, J=8.5, 12.5 Hz, 1H, H5); 4.29(d, J=7.0 Hz, 2H, 9″-CH₂); 4.10 (m, 1H, H9″); 3.65 (s, 3H, OCH₃); 3.28(m, 2H, H8); 3.22 (bs, 1H, NH); 2.58 (s, 3H, 7′″-CH₃); 2.55 (s, 3H,5′″-CH₃); 2.47 (m, 4H, H1′ and H14′″); 2.07 (s, 3H, 8′″-CH₃); 1.91 (m,2H, H7); 1.73 (t, J=6.5 Hz, 2H, H3); 1.60 (m, 2H, H6); 1.25 (s, 6H,2×2′″-CH₃). Mass Spectrum (ES, +ve) m/z 774 (100%) [MH⁺]. HRMS calcd forC₄₁H₅₂N₅O₈S 774.3537, found 774.3524.

Methyl(2R,5R)-2-allyl-5-amino-3-aza-8-[(2,2,5,7,8-pentamethyl-3,4-dihydro-2E-6-chromenylsulfonyl)guanidino]-4-oxooctanoate(40)

The title compound was synthesized using the general N-Fmoc deprotectionprocedure (Procedure C), from 39 (693 mg, 0.900 mmol) to yield 40 (387mg, 0.0700 mmole, 78%) as a cream oil. ¹H NMR (CDCl₃, 300 MHz): δ 7.87(d, J=7.5 Hz, 1H, NH); 6.35 (bs, 3H, NH); 5.67 (m, 1H, H2′); 5.09 (d,J=16.2 Hz, 1H, H3_(a)′); 5.09 (d, J=12.0 Hz, 1H, H3_(b)′); 4.54 (m, 1H,H2); 3.72 (s, 3H, OCH₃); 3.42 (m 1H, H5); 3.19 (d, J=5.4 Hz, 2H, H8);2.56 (s, 3H, 7″-CH₃); 2.54 (s, 3H, 5″-CH₃); 2.51 (m, 2H, H11′); 2.10 (s,3H, 8″-CH₃); 2.05 (bs, 2H, H7); 1.80 (t, J=6.3 Hz, 2H, H2″); 1.57 (m,2H, H6); 1.30 (s, 6H, 2×2″-CH₃). Mass Spectrum (ES, +ve) m/z 552.1 (40%)[MH⁺], 243.0 (100%) [MH⁺ less allylGly]. HRMS calcd for C₂₆H₄₂N₅O₆S552.2856, found 552.2829.

Methyl(2R,5R,8S)-2-allyl-8-(4-allyloxybenzyl)-3,6,9-triaza-5-([{2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl}guanidino]propyl)-4,7,10-trioxoundecanoate(41)

The title compound was synthesised using the general peptide couplingprocedure (Procedure B) using 40 (387 mg, 0.700 mmol) and 16 (153 mg,0.580 mmol) to afford 41 (297 mg, 0.37 mmol, 64%) as a light brownsolid. Mp 217-220° C. ¹H NMR (CDCl₃, 500 MHz): δ 7.22 (bs, 1H, NH); 7.10(d, J=8.0 Hz, 2H, ArH2″″ and ArH6″″); 6.88 (bs, 1H, NH); 6.82 (d, J=8.5Hz, 2H, ArH3″″ and ArH5″″); 6.31 (d, J=7.0 Hz, 1H, NH); 6.17 (bs, 1H,NH); 6.01 (m, 1H, H2′″″); 5.69 (m, 1H, H2′); 5.38 (d, J=17.0 Hz, 1H,H3_(a)′″″); 5.26 (d, J=10 Hz, 1H, H3_(b)′″″); 5.11 (d, J=17.0 Hz, 1H,H3_(a)′); 5.08 (d, J=10.5 Hz, 1H, H3_(b)′); 4.56 (m, 1H, H2); 4.99 (m,3H, H5 and H1′″″); 4.43 (d, J=7.5 Hz, 1H, H8); 3.71 (s, 3H, OCH₃); 3.15(bs, 2H, H3″); 3.00 (m, 2H, ArCH₂); 2.63 (t, J=6.5 Hz, 2H, H4′″); 2.59(s, 3H, 7′″-CH₃); 2.57 (s, 3H, 5′″-CH₃); 2.51 (m, 2H, H1′); 2.11 (s, 3H,8′″-CH₃); 1.97 (s, 3H, H11); 1.80 (t, J=6.5 Hz, 2H, H3′″); 1.58 (s, 6H,2×2′″-CH₃); 1.30 (s, 4H, H1″ and H2″). Mass Spectrum (ES, +ve) m/z 797.4(100%) [M]. HRMS calcd for C₄₀H₅₇N₆O₉S 797.3908, found 797.3915.

(7R,10R,13S,4E/Z)-13-Acetamido-8,11-diaza-10-(3-imino[{2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl}guanidino]propyl)-7-methoxycarbonyl-2-oxa-9,12-dioxo-1(1,4)phenylenacyclotetradecaphane-4-ene(42)

The title compound was prepared using the general procedure for olefinmetathesis (Procedure D), from 41 (170 mg, 0.210 mmol) to yield 42 (160mg, 0.210 mmol, 99%) as a grey solid. Mp 205-207° C. ¹H NMR (CD₃OD, 300MHz): δ 8.05 (m, 2H, NH); 7.02 (m, 2H, ArH); 6.72 (m, 2H, ArH); 6.48(bs, 1H, NH); 5.75 (m, 2H, NH); 5.42 (m, H4 and H5); 4.62 (bs, 2H, H3);4.30 (m, 3H, H7, H10 and H13); 3.66 (s, 3H, OCH₃); 2.90 (m, 4H, H3′ andH14); 2.60 (m, 6H, 5″-CH₃ and 7″-CH₃); 2.55 (m, 2H, H4″); 2.00 (s, 3H,8″-CH₃); 1.75 (s, 3H, NCOCH ₃); 1.55 (m, 2H, H1′); 1.34 (bs, 2H, H3″);1.27 (s, 6H, 2×2″-CH₃). Mass Spectrum (ES, −ve) m/z 769.5 (85%) [M⁺].HRMS calcd for C₃₈H₅₃N₆O₉S 769.3595, found 769.3631.

(7R,10R,13S,4E/Z)-13-Acetamido-8,11-diaza-10-(3-[guanidino]propyl)-7-methoxycarbonyl-2-oxa-9,12-dioxo-1(1,4)phenylenacyclotetradecaphane-4-enehydrochloride (43)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 42 (108 mg, 0.140 mmol) to yield 43 (25mg, 0.049 mmol, 35%) as a white solid. Mp 170-176° C. ¹H NMR (CD₃OD, 300MHz): δ 7.08 (m, 2H, ArH); 6.76 (m, 2H, ArH); 5.90 (m, 1H, H5); 5.54 (m,1H, H4); 4.45 (m, 5H, H3, H7, H10 and H13); 3.69 (m, 3H, OCH₃); 3.07 (m,2H, H3′); 2.92 (m, 2H, H14); 2.49 (m, 2H, H6); 1.94 (s, 3H, NCOCH ₃);1.65 (m, 2H, H1′); 1.33 (m, 2H, H2′). ¹³C NMR (CD₃OD, 75 MHz): δ 173.8,COOCH₃; 173.5, C11; 173.2, C9; 172.6, NCOCH₃; 158.4, CN₃; 157.2, 1-ArC4;131.4, C4; 130.6, C5; 129.7, 1-ArCH2 and 1-ArCH6; 129.3, 1-ArC1; 115.9,1-ArCH3 and 1-ArCH5; 67.3, C3; 57.2, C7; 54.0, C10; 53.7, C13; 53.2,C3′; 52.9, OCH₃; 42.0, C6; 37.9, C14; 35.2, NCOCH₃; 26.1, C1′; 22.6,C2′. Mass Spectrum (ES, +ve) m/z 503 (35%) [M⁺]. HRMS calcd forC₂₄H₃₅N₆O₆ 503.2618, found 503.2644.

Methyl(2R,5S)-2-allyl-3-aza-5-(9H-9-fluorenylmethyloxycarboxamido)-8-[(2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl)guanidino]-4-oxooctanoate(44)

The title compound was synthesized using the general peptide couplingprocedure (Procedure B), from 38 (287 mg, 1.74 mmol) and(2S)-2-(9H-9-fluorenylmethyloxycarboxamido)-8-[(2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl)guanidino]pentanoicacid (961 mg, 1.45 mmol) to afford 44 (1.00 g, 1.29 mmol, 89%) as abrown foam. Mp 90-92° C. ¹H NMR (CDCl₃, 300 MHz): δ 7.70 (d, J=7.6 Hz,2H, ArH1″ and ArH8″); 7.51 (d, J=7.6 Hz, 2H, ArH4″ and ArH5″); 7.33 (t,J=7.2 Hz, 2H, ArH3″ and ArH6″); 7.20 (t, J=7.2 Hz, 2H, ArH2″ and ArH7″);6.42 (d, J=7.6 Hz, 1H, NH); 6.34 (s, 1H, NH); 6.20 (bs, 1H, NH); 5.61(m, 1H, H2′); 5.02 (d, J=18.1 Hz, 1H, H3_(a)′); 4.97 (d, J=10.5 Hz, ¹H,H3_(b)′); 4.53 (dd, J=7.6, 13.1 Hz, 1H, H2); 4.26 (d, J=7.2 Hz, 3H, H5and 9″-CH₂); 4.06 (t, J=7.2 Hz, 1H, H9″); 3.63 (s, 3H, OCH₃); 3.23 (bs,2H, H8); 2.57 (s, 3H, 7′″-CH₃); 2.54 (s, 3H, 5′″-CH₃); 2.47 (m, 4H, H1′and H14′″); 2.07 (s, 3H, 8′″-CH₃); 1.88 (m, 2H, H6); 1.70 (t, J=6.7 Hz,2H, H3′″); 1.60 (m, 2H, H7); 1.23 (s, 6H, 2×2′″-CH₃). Mass Spectrum (ES,+ve) m/z 774 (12%) [MH⁺], 130 (100%) [allylGly]. HRMS calcd forC₄₁H₅₂N₅O₈S 774.3537, found 774.3536.

Methyl(2R,5S)-2-allyl-5-amino-3-aza-8-[(2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl)guanidino]-4-oxooctanoate(45)

The title compound was synthesized using the general N-Fmoc deprotectionprocedure (Procedure C), from 44 (788 mg, 1.01 mmol) to yield 45 (552mg, 1.00 mmole, 99%) as a cream oil. ¹H NMR (CDCl₃, 300 MHz): δ 7.86 (d,J=7.5 Hz, 1H, NH); 6.33 (bs, 3H, NH); 5.69 (m, 1H, H2′); 5.12 (d, J=16.8Hz, 1H, H3_(a)′); 5.11 (d, J=10.8 Hz, 1H, H3_(b)′); 4.53 (dd, J=7.2,12.9 Hz, 1H, H2); 3.71 (s, 3H, OCH₃); 3.41 (d, J=7.2 Hz, 1H, H5); 3.19(m, 2H, H8); 2.57 (m, 2H, H1′); 2.57 (s, 3H, 7″-CH₃); 2.55 (s, 3H,5″-CH₃); 2.10 (s, 3H, 8″-CH₃); 1.80 (m, 4H, H7 and H3″); 1.58 (m, 2H,H6); 1.30 (s, 6H, 2×2″-CH₃). Mass Spectrum (ES, +ve) m/z 552.1 (50%)[MH⁺], 162.7 (100%). HRMS calcd for C₂₆H₄₂N₅O₆S 552.2856, found552.2834.

Methyl(2R,5S,8S)-2-allyl-8-(4-allyloxybenzyl)-3,6,9-triaza-5-([{2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl}guanidino]propyl)-4,7,10-trioxoundecanoate(46)

The title compound was synthesised using the general peptide couplingprocedure (Procedure B), from 45 (513 mg, 0.930 mmol) and 16 (204 mg,0.78 mmol) to afford 46 (496 mg, 0.622 mmol, 80%) as a light brownsolid. Mp 98-102° C. ¹H NMR (CDCl₃, 500 MHz): δ 7.71 (d, J=7.0 Hz, 1H,NH); 7.40 (d, J=7.0 Hz, 1H, NH); 7.06 (d, J=8.5 Hz, 2H, ArH2″″ andArH6″″); 6.99 (bs, 1H, NH); 6.76 (d, J=9.0 Hz, 2H, ArH3″″ and ArH5″″);6.38 (bs, 2H, NH); 6.20 (bs, 1H, NH); 6.02 (m, 1H, H2′″″); 5.69 (m, 1H,H2′); 5.38 (dd, J=1.5, 17.0 Hz, 1H, H3_(a)′″″); 5.25 (dd, J=1.0, 11.0Hz, 1H, H3_(b)′″″); 5.09 (d, J=17.5 Hz, 1H, H3_(a)′); 5.06 (d, J=10.5Hz, 1H, H3_(b)′); 4.66 (m, 1H, H2); 4.55 (m, 2H, H5 and H8); 4.45 (d,J=5.5 Hz, 2H, H1′″″); 3.67 (s, 3H, OCH₃); 3.20 (d, J=4.5 Hz, 2H, H3″);2.97 (m, 2H, ArCH₂); 2.61 (t, J=6.0 Hz, 2H, H4′″); 2.57 (s, 3H,7′″-CH₃); 2.55 (s, 3H, 5′″-CH₃); 2.53 (m, 2H, H1′); 2.09 (s, 3H,8′″-CH₃); 1.88 (s, 3H, H11); 1.79 (t, J=7.0 Hz, 2H, H3′″); 1.74 (m, 2H,H7); 1.57 (m, 2H, H6); 1.30 (s, 6H, 2×2′″-CH₃). Mass Spectrum (ES, +ve)m/z 819 (100%) [MNa⁺]. HRMS calcd for C₄₀H₅₇N₆O₉S 797.3908, found797.3873.

(7R,10S,13S,4E/Z)-13-Acetamido-8,11-diaza-10-(3-imino[{2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl}guanidino]propyl)-7-methoxycarbonyl-2-oxa-9,12-dioxo-1(1,4)phenylenacyclotetradecaphane-4-ene(47)

The title compound was prepared using the general procedure for olefinmetathesis (Procedure D), from 46 (262 mg, 0.330 mmol) to yield 47 (217mg, 0.280 mmol, 86%) as a grey solid. Mp 174-176° C. ¹H NMR (DMSO, 500MHz): δ 8.10 (m, 2H, NH); 7.06 (m, 2H, ArH); 6.73 (m, 2H, ArH); 6.44(bs, 1H, NH); 5.70 (m, 2H, NH); 5.40 (m, H4 and H5); 4.62 (bs, 2H, H3);4.28 (m, 3H, H7, H10 and H13); 3.55 (s, 3H, OCH₃); 3.00 (m, 2H, H3′);2.80 (m, 2H, H14); 2.44 (m, 6H, 5″-CH₃ and 7′″-CH₃); 2.55 (m, 2H, H4″);2.00 (s, 3H, 8″-CH₃); 1.73 (s, 3H, NCOCH₃); 1.51 (m, 2H, H1′); 1.35 (bs,2H, H3″); 1.23 (s, 6H, 2×2″-CH₃). Mass Spectrum (ES, +ve) m/z 767 (65%)[MH⁺]. HRMS calcd for C₃₈H₅₃N₆O₉S 769.3595, found 769.3630.

(7R,10S,13S,4E/Z)-13-Acetamido-8,11-diaza-10-(3-[guanidino]propyl)-7-methoxycarbonyl-2-oxa-9,12-dioxo-1(1,4)phenylenacyclotetradecaphane-4-enehydrochloride (48)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 47 (129 mg, 0.16 mmol) to yield 48 as awhite solid (71 mg, 0.14 mmol, 86%). Mp 134-138° C. ¹H NMR (CD₃OD, 300MHz): δ 7.10 (m, 2H, ArH); 6.78 (m, 2H, ArH); 5.85 (m, 1H, H5); 5.46 (m,1H, H4); 4.43 (m, 5H, H3, H7, H10 and H13); 3.69 (m, 3H, OCH₃); 3.30 (m,2H, H3′); 2.95 (m, 2H, H14); 2.53 (m, 2H, H6); 1.94 (s, 3H, NCOCH ₃);1.80 (m, 2H, H1′); 1.62 (m, 2H, H2′). ¹³C NMR (CD₃OD, 75 MHz): δ 174.0,COOCH₃; 173.6, C11; 173.3, C9; 173.0, NCOCH₃; 158.4, CN₃; 157.2, 1-ArC4;131.3, C4; 130.6, C5; 129.7, 1-ArCH2 and 1-ArCH6; 129.5, 1-ArC1; 115.8,1-ArCH3 and 1-ArCH5; 67.7, C3; 57.8, C7; 54.9, C10; 54.0, C10; 53.2,C3′; 52.9, OCH₃; 42.0, C6; 37.7, C14; 33.2, NCOCH₃; 26.5, C1′; 22.3,C2′. Mass Spectrum (ES, +ve) m/z 503.4 (100%) [M⁺]. HRMS calcd forC₂₄H₃₅N₆O₆ 503.2618, found 503.2666.

Methyl(2R)-2-amino-(4-hydroxyphenyl)-2-propanoate hydrochloride (50)

To a solution of (2R)-2-amino-3-(4-hydroxyphenyl)propanoic acid 49 (1.07g, 5.9 mmol) in anhydrous MeOH (10 mL) at 0° C. was added dropwisethionyl chloride (2 mL). The resulting mixture was allowed to stir for16 h before the solvent was removed by evaporation to yield the titlecompound (1.36 g, 5.9 mmol, 100%) as a white solid, which had spectraldata in agreement with that reported.¹²⁴ [α]_(D) ²³−27.7 (c. 0.1, EtOH).(lit. [α]_(D) ²⁴-27.1 (c. 2.0, MeOH)¹²⁴ Mp 176° C. (lit. 134-136° C.)¹²⁴¹H NMR (CD₃OD, 300 MHz): δ 7.05 (d, J=8.4 Hz, 2H, ArH2′ and ArH6′); 6.82(d, J=8.4 Hz, 2H, ArH3′ and ArH5′); 4.13 (t, J=6.9 Hz, 1H, H2), 3.83 (s,3H, OCH₃); 3.22 (dd, J=6.0, 14.4 Hz, 1H, 3H_(a)); 3.12 (dd, J=6.9, 14.7Hz, 1H, ³H_(b)). Mass Spectrum (CI, +ve) m/z 196 (100%) [M]. HRMS calcdfor C₁₀H₁₄NO₃ 196.0974, found 196.0985.

Methyl(2R)-2-acetamido-3-(4-hydroxyphenyl)propanoate (51)

A solution of the HCl salt 50 (1.09 g, 6.02 mmol) in water (3 mL) wascooled to 0° C. before the addition of 5M sodium acetate solution (35mL) and a small amount of ice. Acetic anhydride (10 mL) was added andthe resulting precipitate was collected by vacuum filtration and driedto yield the title compound (1.09 g, 4.58 mmol, 76%) as a white solid,which had spectral data in agreement with that reported.¹²⁴ [α]_(D) ²⁵−27.2 (c. 0.1, EtOH) (lit. [α]_(D) ²⁵ −26.6 (c. 0.1, MeOH)¹²⁴ Mp132-133° C. (lit. 134-135.5° C.)¹²⁴ ¹H NMR (CDCl₃, 300 MHz): δ 6.94 (d,J=8.4 Hz, 2H, ArH2′ and ArH6′); 6.75 (d, J=8.4 Hz, 2H, ArH3′ and ArH5′);4.77 (m, 1H, H2); 3.71 (s, 3H, OCH₃); 3.04 (dd, J=5.7, 14.1 Hz, 1H,3H1_(a)); 2.95 (dd, J=6.6, 14.1 Hz, 1H, 3H_(b)); 1.96 (s, 3H, NCOCH ₁).Mass Spectrum (CI, +ve) m/z 238 (100%) [MH⁺]. HRMS calcd for C₁₂H₁₆N₁O₄238.107933, found 238.108226.

Methyl(2R)-2-acetamido-3-(4-allyloxyphenyl)propanoate (52)

To a solution of 51 (989 mg, 4.17 mmol), and anhydrous K₂CO₃ (1.15 g,8.34 mmol) in DMF (10 mL) was added allyl bromide (1.01 g, 8.34 mmol)and the resulting mixture was allowed to stir for 16 h under a nitrogenatmosphere. The reaction was quenched with water (30 mL), extracted withethyl acetate (3×30 mL), and the combined organics were washed withwater (5×20 mL) before drying. The solvent was evaporated to yield thetitle compound (985 mg, 3.56 mmol, 85%) as a pale yellow solid. [α]_(D)²⁵ −24.2 (c. 0.1, EtOH). Mp 90° C. ¹H NMR (CDCl₃, 300 MHz): δ 6.97 (d,J=8.7 Hz, 2H, ArH2′ and ArH6′); 6.80 (d, J=8.7 Hz, 2H, ArH3′ and ArH5′);6.09 (d, J=7.8 Hz, 1H, NH); 6.01 (m, 1H, H2″); 5.37 (dd, J=1.8, 17.4 Hz,1H, H3_(a)″); 5.25 (dd, J=1.8, 10.5 Hz, 1H, H3_(b)″); 4.80 (m, 1H, H2);4.47 (d, J=5.5 Hz, 2H, H1″); 3.68 (s, 3H, OCH₃); 3.04 (m, 2H, H3); 1.99(s, 3H, NCOCH ₃). Mass Spectrum (CI, +ve) m/z 278 (100%) [MH⁺]. HRMS(EI) calcd for C₁₅H₁₉NO₄ 277.131408, found 277.130309.

(2R)-2-Acetamido-3-(4-Allyloxyphenyl)propanoic acid (53)

To a solution of 52 (900 mg, 3.25 mmol) in THF/water, 3:1 (10 mL) wasadded lithium hydroxide monohydrate (273 mg, 6.5 mmol), and theresulting suspension was allowed to stir for 16 h. The reaction mixturewas diluted with water (30 mL) and the THF was removed ii vacuo.

The aqueous layer was extracted with diethyl ether (40 mL) to removeunreacted starting material. The aqueous phase was acidified with 10%HCl and the resulting precipitate was extracted with DCM (3×40 mL). Thecombined DCM fractions were dried and evaporated to yield the titlecompound (750 mg, 2.85 mmol, 88%) as a white solid. [α]D²³ −23.2 (c.0.1, EtOH). Mp 75° C. ¹H NMR (D₆ acetone, 300 MHz): δ 7.27 (d, J=7.8 Hz,1H, NH); 7.17 (d, J=8.7 Hz, 2H, ArH2′ and ArH6′); 6.86 (d, J=8.7 Hz, 2H,ArH3′ and ArH5′); 6.06 (m, 1H, H2″); 5.40 (dd J=1.5 Hz, 17.5 Hz, 1H,H3_(a)″); 5.23 (dd, J=1.5, 10.5 Hz, 1H, H3_(b)″); 4.67 (dd, J=5.1, 8.1,10.5 Hz 1H, H2); 4.53 (d, J=5.1 Hz, 2H, H1″); 3.11 (dd, J=5.4, 14.1 Hz,1H, 3H_(a)); 2.93 (dd, J=8.1, 14.1, 1H, 3H_(b)); 1.89 (s, 3H, NCOCH ₃).Mass Spectrum (CI, +ve) m/z 264 (100%) [MH⁺]. HRMS calcd for C₁₄H₁₈NO₄264.123583, found 264.123770.

Methyl(2S,5S,8R)-2-allyl-8-(4-allyloxybenzyl)-3,6,9-triaza-5-([{2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl}guanidino]propyl)-4,7,10-trioxoundecanoate(54)

The title compound was synthesised using the general peptide couplingprocedure (Procedure B), from 34 (654 mg, 1.19 mmol) and 53 (260 mg,0.99 mmol) to afford 54 (683 mg, 0.86 mmol, 87%) as a light brown solid.Mp 200-204° C. ¹H NMR (CDCl₃, 300 MHz): δ 7.10 (d, J=8.4 Hz, 2H, ArH2″″and ArH6″″); 6.90 (d, J=4.8 Hz, 1H, NH); 6.57 (d, J=8.4 Hz, 2H, ArH3″″and ArH5″″); 6.34 (d, J=7.5 Hz, 1H, NH); 6.19 (bs, 2H, NH); 6.00 (m, 1H,H2′″″); 5.70 (m, 1H, H2′); 5.37 (dd, J=1.8, 17.1 Hz, 1H, H3_(a)′″″);5.26 (dd, J=1.8, 10.5 Hz, 1H, H3_(b)′″″); 5.11 (d, J=12.0 Hz, 1H,H3_(a)′); 5.03 (d, J=10.0 Hz, 1H, H3_(b)′); 4.49 (m, 5H, H2, H5, H8 andH1′″″); 3.70 (s, 3H, OCH₃); 3.16 (m, 2H, H3″); 2.99 (m, 2H, ArCH₂); 2.63(t, J=6.3 Hz, 2H, H4′″); 2.59 (s, 3H, 7′″-CH₃); 2.57 (s, 3H, 5′″-CH₃);2.54 (m, 2H, H1′); 2.11 (s, 3H, 8′″-CH₃); 1.96 (s, 3H, H11); 1.80 (t,J=6.3 Hz, 2H, H3′″); 1.72 (m, 2H, H7); 1.58 (m, 2H, H6); 1.30 (s, 6H,2×2′″-CH₃). Mass Spectrum (ES, +ve) m/z 797 (40%) [MH⁺], 106 (100%).HRMS calcd for C₄₀H₅₇N₆O₉S 797.3908, found 797.3926.

(7S,10S,13R,4E/Z)-13-Acetamido-8,11-diaza-10-(3-[{2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl}guanidino]propyl)-7-methoxycarbonyl-2-oxa-9,12-dioxo-1(1,4)phenylenacyclotetradecaphane-4-ene(55)

The title compound was prepared using the general procedure for olefinmetathesis (Procedure D), from 54 (366 mg, 0.46 mmol) to yield 55 (307mg, 0.40 mmol, 87%) as a grey solid. Mp 186-190° C. ¹H NMR (DMSO 500MHz): δ 8.17 (m, 3H, NM; 7.02 (m, 2H, ArH); 6.75 (m, 2H, ArH); 6.41 (bs,1H, NH); 5.75 (m, 1H H5); 5.45 (m, 1H, H4); 4.42 (m, 5H, H3, H7, H10 andH13); 3.69 (s, 3H, OCH₃); 3.06 (m, 2H, H3′); 2.62 (m, 2H, H4″); 2.56 (m,8H, H14, 7″-CH₃, and 5″-CH₃); 2.08 (s, 3H, 8″-CH₃); 1.85 (s, 3H, NCOCH₃); 1.60 (m, 2H, H1′); 1.40 (m, 2H, H3″); 1.26 (s, 6H, 2×2″-CH₃). MassSpectrum (ES, +ve) m/z 769 (40%) [MH⁺], 106 (100%). HRMS calcd forC38H₅₃N₆O₉S 769.3595, found 769.3600.

(7S,10S,13R,4E/Z)-13-Acetamido-8,11-diaza-10-(3-[amino{imino}methylamino]propyl)-7-methoxycarbonyl-2-oxa-9,12-dioxo-1(1,4)phenylenacyclotetradecaphane-4-ene(56)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 55 (128 mg, 0.17 mmol) to yield 56 as ahighly hydroscopic solid (29 mg, 0.058 mmol, 34%). ¹H NMR (CD₃OD, 300MHz): δ 8.19 (m, 3H, NH); 7.63 (bs, 1H, NH); 7.05 (m, 2H, ArH); 6.67 (m,2H, ArH); 5.78 (m, 1H, H5); 5.25 (m, 1H, H4); 4.43 (m, 5H, H3, H7, H10and H13); 3.58 (m, 3H, OCH₃); 3.06 (m, 2H, H3′); 2.85 (m, 2H, H14); 2.51(m, 2H, H6); 1.77 (s, 3H, NCOCH ₃); 1.65 (m, 2H, H11′); 1.37 (m, 2H,H2′). ¹³C NMR (CD₃OD, 75 MHz): δ 171.3, COOCH₃; 171.6, C11; 171.3, C9;169.4, NCOCH₃; 156.8, CN₃; 155.8, 1-ArC4; 130.2, C4; 128.8, C5; 128.2,1-ArCH2 and 1-ArCH6; 127.9, 1-ArC1; 114.9, 1-ArCH3 and 1-ArCH5; 67.1,C3; 55.2, C7; 54.7, C10; 52.9, C10; 51.8, C3′; 51.6, OCH₃; 42.0, C6;36.9, C14; 33.9, NCOCH₃; 29.0, C1′; 22.4, C2′. Mass Spectrum (ES, +ve)m/z 503 (30%) [M⁺], 102 (100%). HRMS calcd for C₂₄H₃₅N₆O₆ 503.2618,found 503.2638.

Methyl(2S)-(4-hydroxyphenyl)-2-tert-butoxycarboxamido propanoate (58)

To a solution of (2S)-2-amino-3-(4-hydroxyphenyl)propanoic acid 57 (5.23g, 28.9 mmol) in anhydrous MeOH (20 mL) at 0° C. was added dropwisethionyl chloride (2 mL). The resulting mixture was allowed to stir for40 h before the solvent was removed by evaporation and the resultinghydrochloride salt was dissolved in DMF (15 mL). To this solution wasadded di-tert-butyl-dicarbonate (9.44 g, 43.3 mmol) and the reactionmixture was allowed to reach RT whilst stirring. After 16 h the reactionwas quenched with water (30 mL) and extracted with EtOAc (3×30 mL). Thecombined organic fractions were washed with water (5×20 mL), dried andevaporated. The crude product was purified by flash columnchromatography (25:1, DCM/MeOH) to yield the title compound (1.32 g,4.48 mmol, 16%) as a yellow oil, which had spectral data in agreementwith that reported.¹²⁵ ¹H NMR (CDCl₃, 300 MHz): δ 6.95 (d, J=8.4 Hz, 2H,ArH2′ and ArH6′); 6.73 (d, J=8.4 Hz, 2H, ArH3′ and ArH5′); 6.51 (bs,OH); 5.05 (d, J=8.4 Hz, 1H, NH); 4.53 (m, 1H, H2), 3.71 (s, 3H, OCH₃);2.99 (m, 2H, H3); 1.42 (s, 9H, C(CH₃)₃). Mass Spectrum (CI, +ve) m/z 196(100%) [MH⁺ (less Boc)]. HRMS calcd for C₁₆H₂₂NO₅ 296.1498, found296.1503.

Methyl(2S)-3-(4-allyloxyphenyl)-2-tert-butoxycarboxamidopropanoate (59)

To a solution of 58 (1.30 g, 4.39 mmol) in DMF (15 mL) under N₂atmosphere was added K₂CO₃ (1.21 g, 8.79 mmol) and the resultingsuspension was allowed to stir for 20 min before the addition of allylbromide (0.76 mL, 8.79 mmol). The reaction mixture was allowed to stirfor 16 h before quenching with water (40 mL) and extracting with EtOAc(3×40 mL). The combined organic fractions were washed with water (4×40mL), dried and evaporated to yield the title compound (1.21 g, 3.35mmol, 76%) as a clear solid, which had spectral data in agreement withthat reported.¹²⁶ Mp 142-144° C. (lit. 145° C.)¹²⁶ ¹H NMR (CDCl₃, 300MHz): δ 7.03 (d, J=8.8 Hz, 2H, ArH2′ and ArH6′); 6.84 (d, J=8.4 Hz, 2H,ArH3′ and ArH5′); 6.04 (m, 1H, H2″); 5.34 (m, 2H, H3″); 4.97 (d, J=8.0Hz, 1H, NH); 4.50 (m, 3H, H1″ and H2); 3.70 (s, 3H, OCH₃); 3.02 (m, 2H,H3); 1.42 (s, 9H, C(CH₃)₃). Mass Spectrum (CI, +ve) m/z 320 (100%)[MH⁺]. HRMS calcd for C₁₇H₂₄N₂O₄ 320.1736, found 320.1714.

Methyl(2S)-2-(4-allyloxyphenyl)-2-aminopropanoate hydrochloride (60)

To a solution of 59 (1.10 g, 3.28 mmol) in DCM (5 mL) was added TFA (5mL) dropwise. After stirring for 16 h the solvent was removed byevaporation and the resulting trifluoroacetate salt was resuspended inmethanol (2 mL) and treated with 1M HCl/diethyl ether (2 mL). Thesolution was stirred for 5 min before the solvent was evaporated toyield the crude hydrochloride salt. The crude product was purified byprecipitation (DCM/diethyl ether) to give the title compound (889 mg,3.28 mmol, 100%) as a white solid. Mp 216-220° C. ¹H NMR (CD₃OD, 300MHz): δ 7.16 (d, J=8.4 Hz, 2H, ArH2′ and ArH6′); 6.93 (d, J=8.8 Hz, 2H,ArH3′ and ArH5′); 6.05 (m, 1H, H2″); 5.38 (dd, J=17.3, 1.7 Hz, 1H,H3_(a)″); 5.24 (dd, J=11.8, 1.3 Hz, 1H, H3_(b)″); 4.54 (m, 2H, H1″);4.26 (m, 1H, H2); 3.81 (s, 3H, OCH₃); 3.14 (m, 2H, H3). ¹³C NMR (CD₃OD,75 MHz): δ 170.3, C1; 159.6, ArC4′; 139.6, C2″; 131.4, ArCH2′ andArCH6′; 127.0, ArC1; 117.4, C3″; 116.2, ArCH3′ and ArCH5′; 69.7, C1″;55.3, C2; 53.6, OCH₃; 36.6, C3. Mass Spectrum (CI, +ve) m/z 236 (90%)[M⁺]. HRMS calcd for C₁₃H₁₅NO₃ 236.1287, found 236.1276.

Methyl(2S,5R)-2-(4-allyloxybenzyl)-3-aza-9-(tert-butoxycarboxamido)-5-(9H-9-fluorenylmethylcarboxamido)-4-oxononanoate(61)

The title compound was synthesized using the general peptide couplingprocedure (Procedure B), from 60 (200 mg, 0.74 mmol) and(2R)-6-tert-butoxycarboxamido-2-[(9H-9-fluorenylmethyloxy)carboxamido]hexanoicacid (291 mg, 0.62 mmol) to afford 61 (317 mg, 0.47 mmol, 75%) as a paleyellow solid. Mp 114-116° C. ¹H NMR (CDCl₃, 300 MHz): δ 7.74 (d, J=7.6Hz, 2H, ArH1′″and ArH8′″); 7.57 (d, J=6.3 Hz, 2H, ArH4′″ and ArH5′″);7.38 (t, J=7.2 Hz, 2H, ArH3′″ and ArH6′″); 7.28 (t, J=7.6 Hz, 2H, ArH2′″and ArH7′″); 6.99 (d, J=7.6 Hz, 2H, ArH2′ and ArH6′); 6.82 (d, J=7.2 Hz,1H, NH); 6.76 (d, J=8.0 Hz, 2H, ArH3′ and ArH5′); 5.97 (m, 1H, H2″);5.67 (d, J=7.2 Hz, 1H, NH); 5.34 (d, J=16.8 Hz, 1H, H3_(a)″); 5.23 (d,J=10.5 Hz, 1H, H3_(b)″); 4.81 (d, J=5.8 Hz, 1H, H2); 4.70 (t, J=5.9 Hz,1H, H5); 4.36 (m, 3H, OCH₂ and OCH ₂—H9′″); 4.19 (m, 2H, H1″); 3.68 (s,3H, OCH₃); 3.05 (m, 4H, H9 and ArCH₂); 1.73 (m, 2H, H6); 1.56 (m, 2H,H7); 1.42 (s, 9HC(CH₃)₃); 1.24 (m, 2H, H8). Mass Spectrum (ES, +ve) m/z708.4 (100%) [MNa⁺]. HRMS calcd for C₃₉H₄₈N₃O₈ 686.3439, found 686.3441.

Methyl(2S,5R)-2-(4-allyloxybenzyl)-5-amino-3-aza-9-(tert-butoxycarboxamido)-4-oxononanoate(62)

The title compound was synthesized using the general N-Fmoc deprotectionprocedure (Procedure C), from 61 (198 mg, 0.290 mmol) to yield 62 (131mg, 0.280 mmole, 97%) as a cream oil. ¹H NMR (CDCl₃, 300 MHz): δ 7.63(d, J=8.4 Hz, 1H, NH); 7.04 (d, J=8.4 Hz, 2H, ArH2′ and ArH6′); 6.83 (d,J=8.4 Hz, 2H, ArH3′ and ArH5′); 6.05 (m, 1H, H2″); 5.40 (dd, J=1.7, 17.3Hz, 1H, H3_(a)″); 5.28 (dd, J=1.7, 11.8 Hz, 1H, H3_(b)″); 4.78 (m, 1H,H2); 4.66 (bs, 1H, NH); 4.50 (m, 2H, H1″); 3.71 (s, 3H, OCH₃); 3.32 (dd,J=4.2, 7.6 Hz, 1H, H5); 2.61 (m, 4H, ArCH₂ and H8); 1.52 (m, 6H, H6, H7and H8); 1.43 (s, 9H, C(CH₃)₃). Mass Spectrum (ES, +ve) m/z 464.3 (100%)[MH⁺]. HRMS calcd for C₂₄H₃₈N₃O₆ 464.2761, found 464.2749.

Methyl(2S,5R,8S)-2,8-di(4-allyloxybenzyl)-3,6,9-triaza-5-(4-[tert-butoxycarboxamido]butyl)-4,7,10-trioxoundecanoate(63)

The title compound was synthesized using the general peptide couplingprocedure (Procedure B), from 62 (220 mg, 0.600 mmol) and 16 (132 mg,0.500 mmol) to yield 63 (130 mg, 0.180 mmol, 37%) as a white solid. Mp185-186° C. ¹H NMR (CDCl₃, 300 MHz): δ 7.36 (d, J=7.6 Hz, 2H, NH); 7.08(d, J=8.4 Hz, 2H, ArH2′ and ArH6′); 7.02 (d, J=8.4 Hz, 2H, ArH2″″ andArH6″″); 6.82 (d, J=8.4 Hz, 4H, ArH3′, ArH5′, ArH3″″ and ArH5″″); 6.63(d, J=7.2 Hz, 1H, NH); 6.02 (m, 2H, H2″ and H2′″″); 5.34 (m, 4H, H3″ andH3′″″); 4.78 (m, 2H, H2 and H8); 4.60 (m, 1H, H5); 4.47 (m, 4H, H1″ andH1′″″); 3.67 (s, 3H, OCH₃); 2.97 (m, 6H, Ar′—CH₂, Ar″″—CH₂ and H14′″);1.93 (s, 3H, H111); 1.43 (s, 9H, C(CH₃)₃); 1.19 (m, 6H, H1′″, H2′″ andH3′″). Mass Spectrum (ES, +ve) m/z 709.3 (100%) [MH⁺]. HRMS calcd forC₃₈H₅₂N₄O₉ 709.3813, found 709.3793.

(10S,13R,16S,4E/Z)-16-Acetamido-11,14-diaza-13-([tert-butoxycarboxamido]butyl)-10-methoxycarbonyl-2,7-dioxa-12,15-dioxo-1(1,4),8(4,1)-diphenylenecycloheptadecaphane-4-ene(64)

The title compound was prepared using the general procedure for olefinmetathesis (Procedure D), from 63 (56 mg, 0.079 mmol) to yield 64 (22mg, 0.032 mmol, 41%) as a brown solid. Mp 190-194° C. ¹H NMR (CDCl₃, 300MHz): δ 6.96 (m, 8H, ArH); 5.93 (m, 2H, H4 and H5); 4.18 (m, 1H, H10);4.83 (m, 1H, H16); 4.56 (m, 4H, H3 and H6); 4.13 (m, 1H, H13); 3.74 (s,3H, OCH₃); 3.28 (m, 2H, H4′); 2.84 (m, 4H, H9 and H17); 1.97 (s, 3H,NCOCH₃); 1.25 (s, 9H, C(CH₃)₃); 1.40 (m, 6H, H1′, H2′ and H3′). MassSpectrum (ES, −ve) m/z 725.4 (100%) [MH⁺+formate], 681 (85%) [MH⁺]. HRMScalcd for C₃₆H₄₉N₄O₉ 681.3500, found 681.3521.

(10S,13R,16S,4E/Z)-16-Acetamido-13-(4-aminobutyl)-11,14-diaza-10-methoxycarbonyl-2,7-dioxa-12,15-dioxo-1(1,4),8(4,1)-diphenylenecycloheptadecaphane-4-ene(65)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 64 (22 mg, 0.038 mmol) to yield 65 (20 mg,0.034 mg, 89%) as a yellow solid. Mp>260° C. ¹H NMR (CD₃OD, 300 MHz): δ8.06 (m, 3H, NH); 7.07 (m, 4H, ArH); 6.78 (m, 4H, ArH); 5.95 (m, 2H, H4and H5); 4.66 (bs, 4H, H3 and H6); 4.56 (m, 1H, H10); 4.40 (m, 1H, H16);4.11 (m, 1H, H13); 3.75 (m, 3H, OCH₃); 2.90 (m, 6H, H9, H17 and H4′);1.92 (s, 3H, NCOCH₃); 1.45 (m, 4H, H1′ and H2′); 0.90 (m, 2H, H3′). ¹³CNMR (CD₃OD, 75 MHz): δ 171.1, C12; 170.3, NCOCH₃; 169.9, 10-CO; 169.4,C15; 157.3, 1-ArC1; 157.13, 8-ArC1; 130.9, 8-ArC4; 130.5, 8-ArCH2 and8-ArCH6; 130.1, 1-ArCH2 and 1-ArCH6; 128.8, C4; 128.4, C5; 126.3,1-ArCH4; 115.5, 8-ArCH3 and 8-ArCH5; 114.4, 1-ArCH3 and 1-ArCH5; 68.6,C3; 67.9, C6; 54.8, C16; 52.6, C13; 52.4, OCH₃; 52.2, C10; 39.5, C4′;38.0, C9′; 35.8, C17; 34.9, C1′; 32.0, C3′; 26.5, 16-NCOCH₃; 23.3, C2′.Mass Spectrum (ES, −ve) m/z 581.6 (100%) [M⁺]. HRMS calcd for C₃₁H₄₁N₃O₇581.2975, found 581.2980.

Methyl(2S,5S)-2-(4-allyloxybenzyl)-3-aza-9-(tert-butoxycarboxamido)-5-(9H-9-fluorenylmethylcarboxamido)-4-oxononanoate(66)

The title compound was synthesized using the general peptide couplingprocedure (Procedure B), from 60 (200 mg, 0.74 mmol) and(2S)-6-tert-butoxycarboxamido-2-[(9H-9-fluorenylmethyloxy)carboxamido]hexanoicacid (291 mg, 0.62 mmol) to afford 66 (328 mg, 0.48 mmol, 77%) as a paleyellow solid. Mp 52-54° C. ¹H NMR (CDCl₃, 300 MHz): δ 7.75 (d, J=7.5 Hz,2H, ArH1′″ and ArH8′″); 7.59 (d, J=6.9 Hz, 2H, ArH4′″ and ArH5′″); 7.39(t, J=7.5 Hz, 2H, ArH3′″ and ArH6′″); 7.30 (dd, J=1.2, 7.5 Hz, 2H,ArH2′″ and ArH7′″); 6.98 (d, J=8.4 Hz, 2H, ArH2′ and ArH6′); 6.77 (d,J=8.7 Hz, 2H, ArH3′ and ArH5′); 6.58 (d, J=7.2 Hz, 1H, NH); 5.98 (m, 1H,H2″); 5.56 (d, J=6.9 Hz, 1H, NH); 5.35 (dd, J=1.5, 17.1 Hz, 1H,H3_(a)″); 5.24 (dd, J=1.5, 10.8 Hz, 1H, H3_(b)″); 4.81 (dd, J=6.0, 13.8Hz, 1H, H2); 4.70 (t, J=5.1 Hz, 1H, H5); 4.40 (m, 4H, H1″ and OCH,—H9′″); 4.20 (d, J=7.2 Hz, 2H, H1″); 3.70 (s, 3H, OCH₃); 3.04 (m, 4H, H9and ArCH₂); 1.80 (m, 2H, H6); 1.64 (m, 2H, H7); 1.43 (s, 9HC(CH₃)₃);1.35 (m, 2H, H8). Mass Spectrum (ES, +ve) m/z 686.4 (10%), 708.4 (100%)[MNa⁺]. HRMS calcd for C₃₉H₄₈N₃O₈ 686.3441, found 686.3454.

Methyl(2S,5R)-2-(4-allyloxybenzyl)-3-aza-5-(9H-9-fluorenylmethylcarboxamido)-4-oxo-8-[(2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl)guanidino]nonanoate(67)

The title compound was synthesized using the general peptide couplingprocedure (Procedure B), from 60 (200 mg, 0.74 mmol) and(2R)-2-(9H-9-fluorenylmethyloxycarboxamido)-8-[(2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl)guanidino]pentanoicacid (411 mg, 0.62 mmol) to afford 67 (386 mg, 0.44 mmol, 71%) as a paleyellow solid. Mp 86° C. ¹H NMR (CDCl₃, 300 MHz): δ 7.70 (d, J=7.5 Hz,2H, ArH1′″ and ArH8′″); 7.52 (d, J=8.7 Hz, 2H, ArH4′″ and ArH5′″); 7.33(dd, J=7.8, 7.8 Hz, 2H, ArH3′″ and ArH6′″); 7.19 (m, 2H, ArH2′″ andArH7′″); 6.90 (d, J=8.1 Hz, 2H, ArH2′ and ArH6′); 6.68 (d, J=8.1 Hz, 2H,ArH3′ and ArH5′); 6.32 (bs, 2H, NH); 6.15 (d, J=8.1 Hz, 1H, NH); 5.91(m, 1H, H2″); 5.29 (d, J=17.4, 1H, H3_(a)″); 5.18 (d, J=10.5 Hz, 1H,H3_(b)″); 4.71 (dd, J=7.8, 13.5 Hz, 1H, H2); 4.26 (m, 5H, H1″, OCH₂—H9′″ and H5); 4.06 (m, 1H, H9′″); 3.62 (s, 3H, OCH₃); 3.17 (m, 2H,H8); 2.98 (m, 2H, ArCH₂); 2.58 (s, 3H, 7″″-CH₃); 2.56 (m, 2H, H4″″);2.55 (s, 3H, 5″″-CH₃); 2.06 (s, 3H, 8″″-CH₃); 1.71 (t, J=6.6 Hz, 2H,H3″″); 1.60 (m, 2H, H6); 1.48 (m, 2H, H7); 1.24 (s, 6H, 2×2″″-CH₃). MassSpectrum (ES, +ve) m/z 880 (100%), [MH⁺]. HRMS calcd for C₄₈H₅₈N₅O₉S880.3955, found 880.3944.

Methyl(2S,5S)-2-(4-allyloxybenzyl)-3-aza-5-(9H-9-fluorenylmethylcarboxamido)-4-oxo-8-[(2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl)guanidino]nonanoate(67)

The title compound was synthesized using the general peptide couplingprocedure (Procedure B), from 60 (200 mg, 0.74 mmol) and(2S)-2-(9H-9-fluorenylmethyloxycarboxamido)-8-[(2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl)guanidino]pentanoicacid (411 mg, 0.62 mmol) to afford 67 (460 mg, 0.52 mmol, 84%) as a paleyellow solid. Mp 88-90° C. ¹H NMR (CDCl₃, 300 MHz): δ 7.70 (d, J=7.8 Hz,2H, ArH1′″ and ArH8′″); 7.53 (d, J=6.6 Hz, 2H, ArH4′″ and ArH5′″); 7.33(m, 2H, ArH3′″ and ArH6′″); 7.18 (m, 2H, ArH2′″ and ArH7′″); 6.98 (d,J=8.1 Hz, 2H, ArH2′ and ArH6′); 6.70 (d, J=8.1 Hz, 2H, ArH3′ and ArH5′);6.34 (bs, 2H, NH); 6.13 (bs, 1H, NH); 5.93 (m, 1H, H2″); 5.30 (dd,J=1.5, 17.1, 1H, H3_(a)″); 5.19 (d, J=1.5, 10.5 Hz, 1H, H3_(b)″); 4.68(m, 1H, H2); 4.30 (m, 5H, H1″, OCH ₂—H9′″ and H5); 4.08 (m, 1H, H9′″);3.60 (s, 3H, OCH₃); 3.21 (m, 2H, H8); 2.97 (m, 2H, ArCH₂); 2.58 (s, 3H,7″″-CH₃); 2.56 (m, 2H, H4″″); 2.54 (s, 3H, 5″″-CH₃); 2.07 (s, 3H,8″″-CH₃); 1.84 (m, 2H, H6); 1.72 (t, J=6.9 Hz, 2H, H3″″); 1.55 (m, 2H,H7); 1.25 (s, 6H, 2×2″″-CH₃). Mass Spectrum (ES, +ve) m/z 880 (30%), 902(100%) [MNa⁺]. HRMS calcd for C₄₈H₅₈N₅O₉S 880.3955, found 880.3943.

Methyl(2S,5R)-2-allyl-3-aza-5-(9H-9-fluorenylmethyloxycarboxamido)-8-(guanidino)-4-oxooctanoatehydrochloride (69)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 28 (81 mg, 0.105 mmol) giving 69 as ahighly hydroscopic solid (43 mg, 0.079 mmol, 75%). Mp 203-208° C. ¹H NMR(CD₃OD, 300 MHz): δ 7.88 (m, 2H, ArH1″ and ArH8″); 7.62 (m, 2H, ArH4″and ArH5″); 7.36 (m, 4H, ArH3″ and ArH6″ and ArH2″ and ArH7″); 5.72 (m,1H, H2′); 5.06 (m, 2H, H3); 4.46 (dd, J=5.4, 8.4 Hz, 1H, H2); 4.39 (d,J=6.3 Hz, 2H, OCH ₂—H9″); 4.31 (m, 1H, H5); 4.19 (m, 1H, H9″); 3.68 (s,3H, OCH₃); 3.17 (bs, 2H, H8); 2.51 (m, Hz, 2H, H1′); 1.79 (m, 2H, H7);1.64 (m, 2H, H6). ¹³C NMR (CD₃OD, 75 MHz): δ 174.1, C4; 172.9, C1;158.4, 5-NCO₂; 146.3, ArC8a″ and ArC9a″; 142.4, ArC4a and ArC4b; 134.1,C2′; 129.1, ArCH3″ and ArCH6″; 128.0, ArCH2″ and ArCH7″; 126.6, ArCH4″and ArCH5″; 120.8, ArCH1″ and ArCH8″; 118.9, C3′; 67.9, CH₂—C9″; 55.8,C9″; 53.4, C2; 52.8, OCH₃; 51.1, C5; 42.0, C8; 36.8, C1′; 30.5, H7;26.3, H6. Mass Spectrum (ES, +ve) m/z 508 (100%) [M⁺]. HRMS calcd forC₂₇H₃₄N₅O₅ 508.2526, found 508.2570.

Methyl(2S,5S)-2-allyl-3-aza-5-(9H-9-fluorenylmethyloxycarboxamido)-8-(guanidino)-4-oxooctanoatehydrochloride (70)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A) using 33 (81 mg, 0.105 mmol) giving 70 (27 mg,0.05 mmol, 47%) as a highly hydroscopic solid. Mp 176-182° C. ¹H NMR(CD₃OD, 500 MHz): δ 7.79 (d, J=7.5 Hz, 2H, ArH1″ and ArH8″); 7.62 (m,2H, ArH4″ and ArH5″); 7.34 (m, 4H, ArH3″ and ArH6″ and ArH2″ and ArH7″);5.77 (m, 1H, H2′); 5.10 (m, 2H, H3′); 4.46 (dd, J=6.0, 8.1 Hz, 1H, H2);4.34 (d, J=7.2 Hz, 2H, OCH, —H9″); 4.32 (m, 1H, H5); 4.19 (m, 1H, H9″);3.69 (s, 3H, OCH₃); 3.20 (m, 2H, H8); 2.52 (m, 2H, H1′); 1.83 (m, 2H,H7); 1.68 (m, 2H, H6). ¹³C NMR (CD₃OD, 75 MHz): δ 174.4, C4; 173.2, C1;158.4, CN₃; 158.3, 5-NCO₂; 144.2, ArC8a″ and ArC9a″; 142.4, ArC4a″ andArC4b″; 134.1, C2′; 129.1, ArCH3″ and ArCH6″; 128.7, ArCH2″ and ArCH7″;126.7, ArCH4″ and ArCH5″; 120.9, ArCH1″ and ArCH8″; 119.0, C3′; 67.9,CH₂—C9″; 55.6, C9″; 53.5, C2; 52.8, OCH₃; 48.1, C5; 42.0, C8; 36.6, C1′;30.3, H7; 26.2, H6. Mass Spectrum (ES, +ve) m/z 508 (100%) [M⁺]. HRMScalcd for C₃₇H₃₄N₅O₅ 508.2560, found 508.2574.

Methyl(2R,5R)-2-allyl-3-aza-5-(9H-9-fluorenylmethyloxycarboxamido)-8-(guanidino)-4-oxooctanoatehydrochloride (71)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 39 (80 mg, 0.10 mmol) to yield 71 as ahighly hydroscopic white solid (45 mg, 0.083 mmol, 80%). ¹H NMR (CD₃OD,500 MHz): δ 7.61 (d, J=7.5 Hz, 2H, ArH1″ and ArH8″); 7.47 (d, J=8.5 Hz,2H, ArH4″ and ArH5″); 7.20 (t, J=7.5 Hz, 2H, ArH3″ and ArH6″); 7.12 (t,J=7.5 Hz, 2H, ArH2″ and ArH7″); 5.58 (m, 1H, H2′); 4.93 (d, J=17.0 Hz,1H, H3_(a)′); 4.87 (d, J=10.0 Hz, 1H, H3_(b)′); 4.28 (dd, J=6.0, 8.0 Hz,1H, H2); 4.20 (d, J=7.0 Hz, 2H, OCH ₂—H9″); 4.03 (t, J=7.0 Hz, 1H, H5);3.99 (t, J=7.0 Hz, 1H, H9″); 3.51 (s, 3H, OCH₃); 3.01 (bs, 2H, H8); 2.34(m, 2H, H1′); 1.64 (bs, 2H, H7); 1.47 (bs, 2H, H6). ¹³C NMR (CD₃OD, 75MHz): δ 174.1, C4; 173.1, C1; 158.4, CN₃; 158.2, 5-NCO₂; 145.1, ArC8a″and ArC9a″; 142.4, ArC4a and ArC4b; 133.9, C2′; 128.6, ArCH3″ andArCH6″; 128.0, ArCH2″ and ArCH7″; 126.0, ArCH4″ and ArCH5″; 120.8,ArCH1″ and ArCH8″; 118.8, C3′; 67.9, CH₂—C9″; 55.6, C9″; 53.6, C2; 52.7,OCH₃; 49.3, C5; 42.1, C8; 36.7, C1′; 30.4, C7; 26.2, C6. Mass Spectrum(ES, +ve) m/z 508 (45%) [M⁺]. HRMS calcd for C₂₇H₃₄N₅O₅ 508.2560, found508.2592.

Methyl(2R,5S)-2-allyl-3-aza-5-(9H-9-fluorenylmethyloxycarboxamido)-8-(guanidino)-4-oxooctanoatehydrochloride (72)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A) using 44 (94 mg, 0.12 mmol) to yield 72 as ahighly hydroscopic white solid (33 mg, 0.061 mmol, 51%). ¹H NMR (CD₃OD,300 MHz): δ 7.79 (d, J=7.5 Hz, 2H, ArH1″ and ArH8″); 7.65 (m, 2H, ArH4″and ArH5″); 7.39 (t, J=7.2 Hz, 2H, ArH3″ and ArH6″); 7.30 (t, J=7.2 Hz,2H, ArH2″ and ArH7″); 5.72 (m, 1H, H2′); 5.09 (d, J=16.5 Hz, 1H,H3_(a)′); 5.04 (d, J=9.6 Hz, 1H, H3_(b)′); 4.46 (dd, J=5.7, 8.4 Hz, 1H,H2); 4.40 (d, J=6.3 Hz, 2H, OCH ₂—H9″); 4.22 (t, J=6.6 Hz, 1H, H5); 4.16(m, 1H, H9″); 3.69 (s, 3H, OCH₃); 3.17 (t, J=6.6 Hz, 2H, H8); 2.51 (m,2H, H1′); 1.80 (m, 2H, H7); 1.62 (m, 2H, H6). ¹³C NMR (CD₃OD, 75 MHz): δ174.0, C4; 172.9, C1; 158.4, CN₃; 158.2, 5-NCO₂; 145.1, ArC8a″ andArC9a″; 142.4, ArC4a″ and ArC4b″; 134.1, C2′; 128.7, ArCH3″ and ArCH6″;128.0, ArCH2″ and ArCH7″; 126.0, ArCH4″ and ArCH5″; 120.8, ArCH1″ andArCH8″; 118.9, C3′; 67.9, CH₂—C9″; 55.8, C9″; 53.4, C2; 52.8, OCH₃;49.3, C5; 42.0, C8; 36.8, C1′; 30.5, C7; 26.3, C6. Mass Spectrum (ES,+ve) m/z 508 (25%) [M⁺], 179 (100%) [Sodium allylglycinamide]. HRMScalcd for C₂₇H₃₄N₅O₅ 508.2560, found 508.2555.

Methyl(2S,5R)-2-(4-allyloxybenzyl)-9-amino-3-aza-5-(9H-9-fluorenylmethyloxycarboxamido)-4-oxononanoatehydrochloride (73)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 61 (132 mg, 0.19 mmol) to yield 73 (92 mg,0.15 mmol, 79%) as a white solid. Mp 162-170° C. ¹H NMR (CD₃OD, 300MHz): δ 8.02 (d, J=8.0 Hz, 1H, NH); 7.79 (d, J=7.6 Hz, 2H, ArH1′″ andArH8′″); 7.64 (t, J=8.4 Hz, 2H, ArH4′″ and ArH5′″); 7.38 (t, J=7.2 Hz,2H, ArH3′″ and ArH6′″); 7.29 (m, 2H, ArH2′″ and ArH7′″); 7.04 (d, J=8.4Hz, 2H, ArH2′ and ArH6′); 6.73 (d, J=8.4 Hz, 2H, ArH3′ and ArH5′); 5.94(m, 1H, H2″); 5.28 (d, J=17.3 Hz, 1H, H3_(a)″); 5.16 (d, J=10.5 Hz, 1H,H3b″); 4.62 (dt, J=5.0, 8.8 Hz, 1H, H5); 4.33 (m, 4H, H1′ and OCH₂—H9′″); 4.19 (t, J=6.7 Hz, 1H, H9′″); 4.07 (dd, J=5.1, 8.0 Hz, 1H, H2);3.70 (s, 3H, OCH₃); 3.11 (m, 2H, H9); 2.90 (m, 2H, ArCH₂); 1.60 (m, 4H,H6 and H7); 1.33 (m, 2H, H8). ¹³C NMR (CD₃OD, 75 MHz): δ 174.2, C4;173.2, C1; 158.1, NCO₂; 145.1, ArC4′; 145.0, ArC8a′″ and ArC9a′″; 142.4,ArC4a′″ and ArC4b′″; 134.7, C2″; 131.1, ArCH2′ and ArCH6′; 129.8,ArCH3′″ and ArCH6′″; 128.7, ArCH2′″ and ArCH7′″; 128.7, ArCH1′″ andArCH8′″; 128.1, ArCH4′″ and ArCH5′″; 120.8, ArC1′; 117.3, C3′; 115.6,ArCH3′ and ArCH5′; 69.6, CH₂—C9′″; 68.0, C1″; 56.1, C5; 55.2, C2; 55.1,OCH₃; 52.8, C9′″; 40.5, C9; 37.3, ArCH₂; 32.6, C6; 28.1, C8; 23.6, C7.Mass Spectrum (ES, +ve) m/z 586.3 (100%) [M⁺]. HRMS calcd for C₃₄H₄₀N₃O₆586.2917, found 586.2935.

Methyl(2S,5S)-2-(4-allyloxybenzyl)-9-amino-3-aza-5-(9H-9-fluorenylmethyloxycarboxamido)-4-oxononanoatehydrochloride (74)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 66 (73 mg, 0.106 mmol) to yield 74 (48 mg,0.07 mmol, 68%) as a white solid. Mp 160-168° C. ¹H NMR (CD₃OD, 300MHz): δ 7.79 (d, J=7.2 Hz, 2H, ArH1′″ and ArH8′″); 7.65 (d, J=7.2 Hz,2H, ArH4′″ and ArH5′″); 7.39 (t, J=7.2 Hz, 2H, ArH3′″ and ArH6′″); 7.29(t, J=7.2 Hz, 2H, ArH2′″ and ArH7′″); 7.07 (d, J=8.4 Hz, 2H, ArH2′ andArH6′); 6.77 (d, J=8.4 Hz, 2H, ArH3′ and ArH5′); 5.96 (m, 1H, H2″); 5.29(dd, J=1.2, 18.3 Hz, 1H, H3_(a)″); 5.16 (dd, J=1.2, 10.5 Hz, 1H, H3b″);4.63 (m, 1H, H5); 4.37 (m, 4H, H1′ and OCH ₂—H9′″); 4.20 (m, 1H, H9′″);4.09 (m, 1H, H2); 3.67 (s, 3H, OCH₃); 3.00 (m, 2H, H9); 2.90 (m, 2H,ArCH₂); 1.65 (m, 4H, H6 and H7); 1.39 (m, 2H, H8). ¹³C NMR (CD₃OD, 125MHz): δ 174.4, C4; 173.3, C1; 158.1, NCO₂; 145.2, ArC4′; 145.0, ArC8a′″and ArC9a′″; 142.4, ArC4a′″ and ArC4b′″; 134.7, C2″; 131.2, ArCH2′ andArCH6′; 129.8, ArCH3′″ and ArCH6′″; 128.8, ArCH2′″ and ArCH7′″; 128.1,ArCH1′″ and ArCH8′″; 126.2, ArCH4′″ and ArCH5′″; 120.9, ArC1′; 117.4,C3′; 115.6, ArCH3′ and ArCH5′; 69.6, CH₂—C9′″; 68.0, C1″; 55.9, C5;55.2, C2; 55.1, OCH₃; 52.8, C9′″; 40.4, C9; 37.3, ArCH₂; 32.4, C6; 27.9,C8; 23.6, C7. Mass Spectrum (ES, +ve) m/z 586.7 (100%) [M⁺]. HRMS calcdfor C₃₄H₄₀N₃O₆ 586.2917, found 586.2925.

Methyl(2S,5R)-2-(4-allyloxybenzyl)-3-aza-5-(9H-9-fluorenylmethylcarboxamido)-8-guanidino-4-oxononanoatehydrochloride (75)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 67 (62 mg, 0.068 mmol) to yield 75 (35 mg,0.054 mmol, 79%) as a white solid. Mp 158-162° C. ¹H NMR (CD₃OD, 300MHz): δ 7.78 (d, J=7.5 Hz, 2H, ArH1′″ and ArH8′″); 7.64 (d, J=8.1 Hz,2H, ArH4′″ and ArH5′″); 7.38 (t, J=6.9 Hz, 2H, ArH3′″ and ArH6′″); 7.37(m, 2H, ArH2′″ and ArH7′″); 7.04 (d, J=8.4 Hz, 2H, ArH2′ and ArH6′);6.72 (d, J=8.4 Hz, 2H, ArH3′ and ArH5′); 5.92 (m, 1H, H2″); 5.28 (d,J=17.1, 1H, H3_(a)″); 5.16 (d, J=10.8 Hz, 1H, H3b″); 4.61 (dd, J=5.1,9.0 Hz, 1H, H2); 4.32 (m, 4H, H1″ and OCH ₂—H9′″); 4.18 (m, 1H, H5);4.09 (m, 1H, H9′″); 3.69 (s, 3H, OCH₃); 3.09 (m, 2H, H8); 2.91 (m, 2H,ArCH₂); 1.62 (m, 2H, H6); 1.51 (m, 2H, H7). ¹³C NMR (CD₃OD, 75 MHz): δ172.0, C4; 171.8, C1 156.8, CN₃; 156.6, ArC4′; 155.9, NCO₂; 143.8,ArC8a′″ and ArC9a′″; 140.8, ArC4a′″ and ArC4b′″; 135.5, C2″; 130.1,ArC1′; 129.6, ArCH4′″ and ArCH5′″; 127.7, ArCH2′″ and ArCH7′″; 127.2,ArCH1′″ and ArCH8′″; 125.4, ArCH3′″ and ArCH6′″; 120.2, ArCH2′ andArCH6′; 117.3, C3″; 114.3, ArCH3′ and ArCH5′; 68.0, C1″; 65.8, CH₂—C9′″;59.3, C9′″; 54.0, C5; 52.0, OCH₃; 46.7, C2; 40.3, C8; 36.1, ArCH₂; 29.1,C6; 24.9, C7. Mass Spectrum (ES, +ve) m/z 614.6 (100%) [M⁺]. HRMS calcdfor C₃₄H₄₀N₅O₆ 614.2979, found 614.3007.

Methyl(2S,5S)-2-(4-allyloxybenzyl)-3-aza-5-(9H-9-fluorenylmethylcarboxamido)-8-guanidino-4-oxononanoatehydrochloride (76)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 68 (93 mg, 0.10 mmol) to yield 76 (54 mg,0.083 mmol, 83%) as a white solid. Mp 170-175° C. ¹H NMR (CD₃OD, 300MHz): δ 7.90 (d, J=7.2 Hz, 2H, ArH1′″ and ArH8′″); 7.75 (m, 2H, ArH4′″and ArH5′″); 7.38 (m, 4H, ArH3′″, ArH6′″, ArH2′″ and ArH7′″); 7.14 (d,J=8.1 Hz, 2H, ArH2′ and ArH6′); 6.82 (d, J=8.1 Hz, 2H, ArH3′ and ArH5′);5.98 (m, 1H, H2″); 5.34 (d, J=17.1, 1H, H3_(a)″); 5.21 (d, J=10.8 Hz,1H, H3_(b)″); 4.46 (m, 2H, H2 and H5); 4.26 (m, 4H, H1″ and OCH ₂—H9′″);4.08 (m, 1H, H9′″); 3.59 (s, 3H, OCH₃); 3.12 (m, 2H, H8); 2.94 (m, 2H,ArCH₂); 1.69 (m, 2H, H6); 1.52 (m, 2H, H7). ¹³C NMR (CD₃OD, 75 MHz): δ171.9, C4; 171.8, C1 157.0, CN₃; 156.6, ArC4′; 155.9, NCO₂; 143.9,ArC8a′″ and ArC9a′″; 140.7, ArC4a′″ and ArC4b′″; 133.8, C2″; 130.1,ArC1′; 129.0, ArCH4′″ and ArCH5′″; 127.7, ArCH2′″ and ArCH7′″; 127.1,ArCH1′″ and ArCH8′″; 125.4, ArCH3′″ and ArCH6′″; 120.1, ArCH2′ andArCH6′; 117.3, C3″; 114.4, ArCH3′ and ArCH5′; 68.1, C1″; 65.7, CH₂—C9′″;59.3, C9′″; 53.9, C5; 51.8, OCH₃; 46.7, C2; 40.3, C8; 35.7, ArCH₂; 29.0,C6; 25.1, C7. Mass Spectrum (ES, +ve) m/z 614.8 (100%) [M⁺]. HRMS calcdfor C₃₄H₄₀N₅O₆ 614.2979, found 614.2972.

Methyl(2S,5R,8S)-2-allyl-8-(4-allyloxyphenyl)-5-(4-aminobutyl)-3,6,9-triaza-4,7,10-trioxoundecanoatehydrochloride (77)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 21 (64 mg, 0.11 mmol) to yield 77 (22 mg,0.041 mmol, 37%) as a cream highly hydroscopic solid. ¹H NMR (CD₃OD, 500MHz): δ 7.15 (d, J=8.0 Hz, 2H, ArH2′″ and ArH6′″); 6.87 (d, J=8.0 Hz,2H, ArH3′″ and ArH5′″); 6.05 (m, 1H, H2″″); 5.73 (m, 1H, H2′); 5.39 (d,J=17.0 Hz, 1H, H3″″); 5.24 (d, J=10.5 Hz, 1H, H3″″); 5.08 (d, J=17.0 Hz,1H, H3′); 5.04 (d, J=10.0 Hz, 1H, H3′); 4.52 (d, J=5.5 Hz, 2H, H1″″);4.44 (m, 2H, H2 and H5); 4.15 (d, J=6.5 Hz, 1H, H8); 3.69 (s, 3H, OCH₃);2.92 (m, 2H, H11′); 2.83 (bs, 2H, H4″); 2.54 (m, 2H, ArCH₂); 1.93 (s,3H, H11); 1.74 (bs, 2H, H1″); 1.50 (bs, 2H, H2″); 1.00 (bs, 2H, H3″).¹³C NMR (CD₃OD, 75 MHz): δ 174.3, C7; 173.7, C1; 173.2, C4; 173.1, C10;158.8, ArC4′″; 134.8, C2′; 134.5, C2″″; 131.3, ArCH2′″ and ArCH6′″;129.9, ArC1′″; 118.4, C3′; 117.5, C3″″; 115.8, ArCH3′″ and ArCH5′″;69.8, C1″″; 57.6, C5; 54.2, OCH₃; 53.8, C8; 52.7, C2; 40.3, C4′; 37.4,ArCH₂; 36.4, C1′; 31.7, C1″; 28.0, C3″; 23.5, C11; 22.4, C2″. MassSpectrum (ES, +ve) m/z 503.7 (100%) [M⁺]. HRMS calcd for C₂₆H₃₉N₄O₆503.2870, found 503.2881.

Methyl(2S,5S,8S)-8-acetamido-2-allyl-9-(4-allyloxyphenyl)-5-(4-aminobutyl)-3,6-diaza-4,7-dioxononanoatehydrochloride (78)

The title compound was synthesized using the general procedure(Procedure A), by deprotection of 25 (104 mg, 0.170 mmol) to yield 78 asa 1:1 mixture of epimers (55 mg, 0.10 mmol, 60%) as a highly hydroscopicyellow solid. Mp 150-154° C. ¹H NMR (CD₃OD, 300 MHz): δ 7.14 (d, J=8.0Hz, 2H, ArH2′″ and ArH6′″); 6.84 (t, J=8.0 Hz, 2H, ArH3′″ and ArH5′″);6.03 (m, 1H, H2″″); 5.76 (m, 1H, H2′); 5.37 (d, J=17.3 Hz, 1H,H3_(a)″″); 5.22 (d, J=9.7 Hz, 1H, H3_(b)″″); 5.10 (m, 2H, H3′); 4.53 (m,5H, H2, H5, H8 and H1″″); 3.69/3.67 (s, 3H, OCH₃); 2.87 (m, 4H, H1′ andH4″); 2.54 (m, 2H, ArCH₂); 1.93/1.91 (s, 3H, H11); 1.50 (s, 6H, H1″, H2″and H3″). ¹³C NMR (CD₃OD, 75 MHz): δ 173.7/173.6, C7; 173.4, C1; 173.1,C4; 173.0/172.9, C10; 158.7, ArCH4′″; 134.8, C2′; 134.3/134.0, C2″″;131.2/131.1, ArCH2′″ and ArCH6′″; 130.2/130.1, ArC1′″; 118.8/118.5, C3′;117.4/117.3, C3″″; 115.7/115.6, ArCH3′″ and ArCH5′″; 69.8/69.7, C1″″;57.2, C5; 54.0, OCH₃; 53.8/53.7, C8; 52.8/52.7, C2; 40.6/40.5, C4′;37.8/37.7, ArCH₂; 36.6/36.5, C1′; 31.9, C1″; 28.0, C3″; 23.4, C11; 22.5,C2″. Mass Spectrum (ES, +ve) m/z 503.3 (100%) [M⁺]. HRMS calcd forC₂₆H₃₉N₄O₆ 503.2870, found 503.2894.

Methyl(2R,5R,8S)-2-allyl-8-(4-allyloxybenzyl)-3,6,9-triaza-5-(3-[guanidino)-4,7,10-oxoundecanoatehydrochloride (79)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 41 (48 mg, 0.60 mmol) to yield 79 as ahighly hydroscopic solid (32 mg, 0.060 mmol, 100%). ¹H NMR (CD₃OD, 300MHz): δ 7.15 (d, J=8.4 Hz, 2H, ArH2′″ and ArH6′″); 6.86 (d, J=8.7 Hz,2H, ArH3′″ and ArC5′″); 6.04 (m, 1H, H2″″); 5.77 (m, 1H, H2′); 5.38 (dd,J=1.5, 17.4 Hz, 1H, H3_(a)″″); 5.23 (dd, J=1.2, 10.5 Hz, 1H, H3_(b)″″);5.09 (dd, J=1.2, 16.8 Hz, 1H, H3_(a)′); 5.06 (d, J=10.6 Hz, 1H,H3_(b)′); 4.50 (m, 4H, H2″″ and H2); 4.39 (dd, J=5.7, 8.1 Hz, 1H, H5);4.26 (dd, J=4.5, 8.7 Hz, 1H, H8); 3.68 (s, 3H, OCH₃); 3.07 (t, J=7.2 Hz,2H, H3″); 2.94 (m, 2H, ArCH₂); 2.54 (m, 2H, H1′); 1.95 (s, 3H, H11);1.62 (m, 2H, H1″); 1.32 (m, 2H, H2″). ¹³C NMR (CD₃OD, 75 MHz): δ 173.7,C4; 173.6, C11; 173.4, C1; 172.9, C7; 158.8, ArC4′″; 158.4, CN₃; 134.8,C2″″; 134.3, C2′; 131.2, ArC1′″; 130.0, ArCH2′″ and ArCH6′″; 118.6, C3′;117.4, C3″″; 115.7, ArCH3′″ and ArCH5′″; 69.8, C1″″; 57.2, C2; 53.8, C5;53.8, C8; 52.8, OCH₃; 50.1, C3″; 37.7, ArCH₂; 36.5, C1′; 29.7, C2″;22.9, C11; 22.3, C1″. Mass Spectrum (ES, +ve) m/z 531.5 (80%) [M⁺]. HRMScalcd for C₂₆H₃₉N₆O₆ 531.2931, found 531.2936.

Methyl(2R,5S,8S)-2-allyl-8-(4-allyloxybenzyl)-3,6,9-triaza-5-(3-[guanidino)-4,7,10-oxoundecanoatehydrochloride (80)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 46 (87 mg, 0.11 mmol) to yield 80 as ahighly hydroscopic solid (35 mg, 0.062 mmol, 56%). ¹H NMR (CD₃OD, 300MHz): δ 7.16 (d, J=8.5 Hz, 2H, ArH2′″ and ArH6′″); 6.83 (d, J=8.0 Hz,2H, ArH3′″ and ArH5′″); 6.04 (m, 1H, H2″″); 5.74 (m, 1H, H2′); 5.38 (dd,J=1.5, 17.5 Hz, 1H, H3_(a)″″); 5.23 (dd, J=1.0, 10.5 Hz, 1H, H3_(b)″″);5.12 (d, J=17.0 Hz, 1H, H3_(a)′); 5.08 (d, J=10.5 Hz, 1H, H3_(b)′); 4.50(d, J=5.0 Hz, 2H, H1″″); 4.43 (m, H2, H5 and H8); 3.71 (s, 3H, OCH₃);2.97 (t, J=7.5 Hz, 2H, H3″); 2.94 (m, 2H, ArCH₂); 2.52 (m, 2H, H1′);1.93 (s, 3H, CH₃, H11); 1.78 (m, 2H, H1″); 1.61 (m, 2H, H2″). ¹³C NMR(CD₃OD, 75 MHz): δ 173.9, C4; 173.4, C11; 173.1, C1; 172.9, C7; 158.8,ArC4′″; 158.4, CN₃; 134.8, C2″″; 134.1, C2′; 131.1, ArC1′″; 130.2,ArCH2′″ and ArCH6′″; 118.9, C3′; 117.2, C3″″; 115.6, ArCH3′″ andArCH5′″; 69.7, C1″″; 56.9, C2; 53.8, C5; 53.6, C8; 52.8, OCH₃; 50.1,C3″; 37.7, ArCH₂; 36.9, C1′; 26.1, C2″; 22.5, C11; 20.7, C1″. MassSpectrum (ES, +ve) m/z 531.1 (85%) [M⁺]. HRMS calcd for C₂₆H₃₉N₆O₆531.2931, found 531.2952.

Methyl(2S,5S,8S)-2-allyl-8-(4-allyloxybenzyl)-3,6,9-triaza-5-(3-[guanidino]propyl)-4,7,10-oxoundecanoatehydrochloride (81)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 36 (63 mg, 0.079 mmol) to yield 81 as ahighly hydroscopic solid (38 mg, 0.036 mmol, 85%). ¹H NMR (CD₃OD, 300MHz): δ 7.13 (d, J=8.7 Hz, 2H, ArH2′″ and ArH6′″); 6.82 (d, J=8.7 Hz,2H, ArH3′″ and ArH5′″); 6.03 (m, 1H, H2″″); 5.77 (m, 1H, H2′); 5.36 (dd,J=1.5, 17.4 Hz, 1H, H3_(a)″″); 5.22 (dd, J=1.5, 10.5 Hz, 1H, H3_(b)″″);5.13 (d, J=18.3 Hz, 1H, H3_(a)′); 5.08 (d, J=9.6 Hz, 1H, H3_(b)′); 4.49(m, 3H, H1″″ and H5); 4.40 (m, 2H, H2 and H8); 3.69 (s, 3H, OCH₃); 3.18(m, 2H, H3″); 3.02 (dd, J=5.7, 13.8 Hz, 1H, ArCH); 2.82 (dd, J=9.0, 14.1Hz, 1H, ArCHH; 2.51 (m, 2H, H1′); 1.92 (s, 3H, H11); 1.83 (m, 2H, H1″);1.64 (m, 2H, H2″). ¹³C NMR (CD₃OD, 75 MHz): δ 173.9, C4; 173.5, C11;173.4, C1; 173.2, C7; 158.8, ArC4′″; 158.4, CN₃; 134.9, C2″″; 134.2,C2′; 131.2, ArC1′″; 130.3, ArCH2′″ and ArCH6′″; 117.4, C3′; 116.2, C3″″;115.6, ArCH3′″ and ArCH5′″; 69.7, C1″″; 56.6, C2; 53.8, C5; 53.6, C8;52.8, OCH₃; 50.1, C3″; 36.6, ArCH₂; 36.5, C1′; 30.3, C2″; 23.0, C11;22.5, C1″. Mass Spectrum (ES, +ve) m/z 531.1 (100%) [M⁺]. HRMS calcd forC₂₆H₃₉N₆O₆ 531.2931, found 531.2916.

Methyl(2S,5R,8S)-2-allyl-8-(4-allyloxybenzyl)-3,6,9-triaza-5-(3-[guanidino]propyl)-4,7,10-oxoundecanoatehydrochloride (82)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 30 (70 mg, 0.088 mmol) to yield 82 as ahighly hydroscopic solid (37 mg, 0.065 mmol, 74%). ¹H NMR (CD₃OD, 300MHz): δ 7.12 (d, J=7.5 Hz, 2H, ArH2′″ and ArH6′″); 6.83 (d, J=7.5 Hz,2H, ArH3′″ and ArC5′″); 6.01 (m, 1H, H2″″); 5.69 (m, 1H, H2′); 5.35 (d,J=17.4 Hz, 1H, H3_(a)″″); 5.19 (d, J=9.9 Hz, 1H, H3_(b)″″); 5.09 (m, 2H,H3′); 4.47 (m, 2H, H2″″); 4.40 (m, 2H, H2 and H5); 4.16 (m, 1H, H8);3.65 (s, 3H, OCH₃); 3.31 (m, 2H, H3″); 2.95 (m, 2H, ArCH₂); 2.50 (m, 2H,H1′); 1.92 (s, 3H, H11); 1.74 (m, 2H, H1″); 1.23 (m, 2H, H2″). ¹³C NMR(CD₃OD, 75 MHz): δ 174.0, C4; 173.4, Cl₁; 172.9, C1; 169.0, C7; 158.8,ArC4′″; 158.2, CN₃; 134.7, C2″″; 134.3, C2′; 131.2, ArC1′″; 129.8,ArCH2′″ and ArCH6′″; 118.4, C3′; 117.4, C3″″; 115.7, ArCH3′″ andArCH5′″; 69.8, C1″″; 57.7, C2; 54.0, C5; 53.7, C8; 52.8, OCH₃; 50.1,C3″; 37.5, ArCH₂; 36.4, C1′; 29.5, C2″; 24.0, C11; 22.3, C1″. MassSpectrum (ES, +ve) m/z 531 (100%) [M⁺]. HRMS calcd for C₂₆H₃₉N₆O₆531.2931, found 531.2939.

Methyl(2S,5R,8S)-2,8-di(4-allyloxybenzyl)-5-(4-aminobutyl)-3,6,9-triaza-4,7,10-trioxoundecanoatehydrochloride (83)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 63 (33 mg, 0.051 mmol) to yield 83 (18 mg,0.028 mmol, 55%) as a yellow solid. Mp 186-190° C. ¹H NMR (CD₃OD, 500MHz): δ 7.50 (bs, 1H, NH); 7.41 (m, 4H, ArH); 7.17 (m, 4H, ArH); 6.38(m, 2H, H2″ and H12′″″); 5.64 (m, 4H, H3″ and H3′″″); 4.83 (m, 6H, H2,H8, H1″ and H1′″″); 4.51 (m, 1H, H5); 3.70 (s, 3H, OCH₃); 3.28 (m, 6H,H4′″, Ar′—CH₂ and Ar″″—CH₂); 2.27 (s, 3H, H111); 1.87 (m, 4H, H1″ andH3″); 1.33 (m, 2H, H2″). ¹³C NMR (CD₃OD, 125 MHz): δ 173.9, C7; 173.7,C4; 173.1, C1; 172.0, C10; 158.5, ArC4″″ and ArC4′; 134.7, C2″ andC2′″″; 131.3, ArCH2′ and ArCH6′; 131.1, ArCH2″″ and ArCH6″″; 130.0,ArC1″″; 129.8, ArC1′; 117.8, C3″; 117.5, C3′″″; 115.8, ArCH3′ andArCH5′; 115.6, ArCH3″″ and ArCH5″″; 70.0, C1″; 69.8, C1′″″; 57.2, C2;55.2, C5; 53.8, OCH₃; 52.4, C8; 40.7, C4′″; 37.4, Ar′—CH₂; 37.1,Ar″″—CH₂; 31.7, C1′″; 27.9, C3′″; 23.2, C11; 22.2, C2′″. Mass Spectrum(ES, +ve) m/z 609.7 (100%) [M⁺]. HRMS calcd for C₃₃H₄₅N₄O₇ 609.3288,found 609.3301.

Methyl(2S,5R,8S)-2-allyl-8-(4-allyloxybenzyl)-3,6,9-triaza-5-(4-[{N,N-di-tert-butoxycarbonyl}guanidino]butyl)-4,7,10-trioxoundecanoate(84)

To a solution of 21 (56 mg, 0.093 mmol) in DCM (2 mL) was added TFA (2mL) and the resulting mixture was allowed to stir for 3 h. The solventwas concentrated and the intermediate trifluoroacetate salt wasprecipitated by addition of diethyl ether and collected as a solid byvacuum filtration. To this solid was addedN-tert-butoxycarboxamido(trifluoromethylsulfonylimino)methyl propanamide(65 mg, 0.17 mmol), triethylamine (0.2 mL) and DCM (2 mL). The resultingsolution was allowed to stir for 16 h under N₂. The solvent wasevaporated and the crude product was purified by flash columnchromatography (15:1, DCM/MeOH) to yield the title compound as a 1:1mixture of epimers (70 mg, 0.093 mmole, 100%) as an orange/yellow solid.Mp 112-114° C. ¹H NMR (CDCl₃, 300 MHz): δ 8.31 (bs, 1H, NH); 7.20 (d,J=8.0 Hz, 1H, NH); 7.08 (m, 2H, ArH2′″ and ArH6′″); 6.94 (d, J=7.6 Hz,1H, NH); 6.84 (m, 2H, ArH3′″ and ArH5′″); 6.72 (d, J=7.2 Hz, 1H, NH);6.60 (d, J=7.6 Hz, 1H, NH); 6.02 (m, 1H, H2″″); 5.65 (m, 1H, H2′); 5.38(d, J=17.3 Hz, 1H, H3_(a)″″); 5.26 (d, J=10.5 Hz, 1H, H3_(b)″″); 5.11(m, 2H, H3′); 4.52 (m, 5H, H2, H5, H8 and H2″″); 3.74/3.70 (s, 3H,OCH₃); 3.32 (d, J=6.7 Hz, 2H, H4″); 2.95 (m, 2H, ArCH₂); 2.50 (m, 2H,H1′); 1.97./1.96 (s, 3H, H₁₁); 1.37 (m, 6H, H1″, H2″ and H3″); 1.49 (s,18H, 2×C(CH₃)₃). Mass Spectrum (ES, +ve) m/z 745.4 (100%) [MH⁺]. HRMScalcd for C₃₇H₅₇N₆O₁₀ 745.4136, found 745.4138.

Methyl(2S,5S,8S)-2-allyl-8-(4-allyloxybenzyl)-3,6,9-triaza-5-(4-[{N,N-di-tert-butoxycarbonyl}guanidino]butyl)-4,7,10-trioxoundecanoate(85)

To a solution of 25 (41 mg, 0.081 mmol) in DCM (2 mL) was addedN-tert-butoxycarboxamido (trifluoromethylsulfonylimino)methylpropanamide (35 mg, 0.089 mmol), triethylamine (0.1 mL). The resultingsolution was allowed to stir for 16 h under N₂. The solvent wasevaporated and the crude product was purified by flash columnchromatography (15:1, DCM/MeOH) to yield the title compound as a 1:1mixture of epimers (45 mg, 0.060 mmole, 74%) as an orange/yellow solid.Mp 114-118° C. ¹H NMR (CDCl₃, 300 MHz): δ 8.26 (bs, 1H, NH); 7.08 (t,J=8.4 Hz, 2H, ArH2′″ and ArH6′″); 6.97 (m, 1H, NH); 6.83 (t, J=8.4 Hz,2H, ArH3′″ and ArH5′″); 6.73 (d, J=8.0 Hz, 1H, NH); 6.57 (t, J=9.3 Hz,1H, NH); 6.03 (m, 1H, H2″″); 5.66 (m, 1H, H2′); 5.39 (d, J=17.3 Hz, 1H,H3_(a)″″); 5.26 (d, J=10.1 Hz, 1H, H3_(b)″″); 5.10 (m, 2H, H3′); 4.51(m, 5H, H2, H5, H8 and H1″″); 3.74/3.71 (s, 3H, OCH₃); 3.33 (bs, 2H,H4″); 2.96 (m, 2H, H1′); 2.52 (m, 2H, ArCH₂); 1.97 (s, 3H, H₁₁); 1.47(m, 6H, H1″, H2″ and H3″); 1.49 (s, 18H, C(CH ₃)₃). Mass Spectrum (ES,+ve) m/z 745.2 (100%) [MH⁺]. HRMS calcd for C₃₇H₅₇N₆O₁₀ 745.4136, found745.4105.

(7S,10S,13S,4E/Z)-13-Acetamido-8,11-diaza-10-(4-[{N,N-di-tert-butoxycarbonyl}guanidino]butyl)-7-methoxycarbonyl-2-oxa-9,12-dioxo-1(1,4)phenylenacyclotetradecaphane-4-ene(86)

To a solution of 26 (75 mg, 0.15 mmol) in DCM (2 mL) was addedN-tert-butoxycarboxamido(trifluoromethylsulfonylimino)methyl propanamide(115 mg, 0.29 mmol), triethylamine (0.1 mL) and DCM (2 mL). Theresulting solution was allowed to stir for 16 h under N₂. The solventwas evaporated and the crude product was purified by flash columnchromatography (15:1, DCM/MeOH) to yield 86 as a 1:1 mixture of epimers(96 mg, 0.13 mmole, 87%) as an orange/yellow solid. Mp 104-102° C. ¹HNMR (CDCl₃, 300 MHz): δ 8.26 (m, 1H, NH); 6.89 (m, 4H, ArH); 5.63 (m,2H, H4 and H5); 4.65 (m, 5H, H2, H7, H10 and H13); 3.79/3.78 (s, 3H,OCH₃); 3.30 (m, 2H, H4′); 2.92 (m, 2H, H6); 2.67 (m, 2H, H14); 2.09/2.07(s, 3H, NCOCH ₃); 1.55 (m, 6H, H1′, H2′ and H3′); 1.49/1.48 (s, 18H,C(CH₃)₃). Mass Spectrum (ES, +ve) m/z 717.4 (100%) [MH⁺]. HRMS calcd forC₃₅H₅₃N₆O₁₀ 717.3823, found 717.3806.

Methyl(2S,5R,8S)-2-allyl-9-(4-allyloxybenzyl)-5-(4-[guanidino]butyl)-3,6,9-triaza-4,7,10-trioxoundecanoatehydrochloride (87)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 84 (71 mg, 0.095 mmol) to yield 87 (43 mg,0.074 mmol, 78%) as a yellow hydroscopic solid. ¹H NMR (CD₃OD, 300 MHz):δ 8.20 (m, 2H, NH×2); 7.15 (d, J=8.4 Hz, 2H, ArH2′″ and ArH6′″); 6.87(d, J=8.4 Hz, 2H, ArH3′″ and ArH5′″); 6.03 (m, 1H, H2″″); 5.73 (m, 1H,H2′); 5.39 (d, J=17.3 Hz, 1H, H3_(a)″″); 5.24 (d, J=10.5 Hz, 1H,H3_(b)″″); 5.12 (d, J=6.0 Hz, 1H, H3_(a)′); 5.05 (d, J=9.9 Hz, 1H,H3_(b)′); 4.45 (m, 4H, H2, H5 and H11″″); 4.17 (dd, J=4.0, 8.7 Hz, 1H,H8); 3.72 (s, 3H, OCH₃); 2.99 (m, 4H, H1′ and H4″); 2.53 (m, 2H, ArCH₂);1.94 (s, 3H, H11); 1.59 (m, 4H, H2″ and H3″); 1.00 (m, 2H, H1″). ¹³C NMR(CD₃OD, 75 MHz): δ 174.3, C4; 174.0, C11; 173.3, C1; 173.2, C7; 159.0,ArC4′″; 158.5, CN₃; 134.9, C2″″; 134.5, C2′; 131.4, ArC1′″; 130.4,ArCH2′″ and ArCH6′″; 118.6, C3′; 117.5, C3″″; 115.9, ArCH3′″ andArCH5′″; 69.8, C1″″; 57.5, C2; 54.3, C5; 53.8, C8; 52.7, OCH₃; 42.1,C4″; 37.5, ArCH₂; 36.4, C1′; 31.9, C2″; 29.2, C3″; 23.6, C11; 22.4, C1″.Mass Spectrum (ES, +ve) m/z 545.4 (100%) [M⁺]. HRMS calcd for C₂₇H₄₁N₆O₆545.3088, found 545.3073.

Methyl(2S,5S,8S)-2-allyl-9-(4-allyloxyphenyl)-5-(4-[guanidino]butyl)-3,6,9-triaza-4,7,10-trioxoundecanoatehydrochloride (88)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 85 (40 mg, 0.054 mmol) to yield 88 (11 mg,0.019 mmol, 35%) as a highly hydroscopic yellow solid. ¹H NMR (CD₃OD,300 MHz): δ 7.10 (bs, 2H, ArH2′″ and ArH6′″); 6.79 (bs, 2H, ArH3′″ andArH5′″); 6.00 (m, 1H, H2″″); 5.72 (m, 1H, H2′); 5.16 (m, 4H, H3″″ andH3′); 4.40 (m, 5H, H2, H5, H8 and H1″″); 3.65 (s, 3H, OCH₃); 3.00 (m,4H, H1′ and H4″); 2.49 (bs, 2H, ArCH₂); 1.87 (s, 3H, H11); 1.36 (m, 6H,H1″, H2″ and H3″). ¹³C NMR (CD₃OD, 75 MHz): δ 174.2, C4; 174.1, C11;173.6, C1; 173.2, C7; 159.4, ArC4′″; 158.4, CN₃; 134.6, C2″″; 134.2,C2′; 131.2, ArC1′″; 130.3, ArCH2′″ and ArCH6′″; 119.6, C3′; 118.2, C3″″;116.3, ArCH3′″ and ArCH5′″; 70.0, C1″″; 57.4, C2; 54.4, C5; 53.9, C8;52.4, OCH₃; 42.2, C4″; 37.6, ArCH₂; 36.6, C1′; 32.5, C2″; 29.5, C3″;23.6, C11; 22.8, C1″. Mass Spectrum (ES, +ve) m/z 545.3 (100%) [M⁺].HRMS calcd for C₂₇H₄₁N₆O₆ 545.3088, found 545.3066.

(7S,10S,13S,4E/Z)-13-Acetamido-10-(4-[guanidino]butyl)-8,11-diaza-7-methoxycarbonyl-2-oxa-9,12-dioxo-1(1,4)phenylenacyclotetradecaphane-4-enehydrochloride (89)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 86 (86 mg, 0.12 mmol) to yield 89 (50 mg,0.097 mmol, 81%) as a highly hydroscopic yellow solid. ¹H NMR (CD₃OD,500 MHz): δ 10.34 (bs, 1H, NH); 0.42 (m, 2H, ArH); 7.08 (m, 2H, ArH);5.97 (m, 2H, H4 and H5); 4.80 (m, 5H, H2, H7, H10 and H13); 3.65 (s, 3H,OCH₃); 3.32 (m, 2H, H4′); 3.09 (m, 2H, H6); 2.42 (m, 2H, H14); 2.10 (s,3H, NCOCH ₃); 2.04 (m, 2H, H3′); 1.86 (m, 2H, H1′); 1.50 (m, 2H, H2′).¹³C NMR (CD₃OD, 125 MHz): δ 173.3/173.2, C9; 172.7/173.6, 7-CO; 172.5,13-NCO; 169.4, C12; 158.5/158.4, 1-ArC1; 131.4/131.3, 1-ArCH2 and1-ArCH6; 131.0, C4; 129.3, C5; 129.0, 1-ArC4; 116.5, 1-ArCH3 and1-ArCH5; 67.0, C3; 58.2, C7; 57.5, C13; 57.4, C10; 53.9, OCH₃; 42.1,C4′; 33.9, C14; 29.0, C6; 23.5, C3′; 22.7, C1′; 22.5, NCOCH₃; 22.5, C2′.Mass Spectrum (ES, +ve) m/z 517.4 (100%) [M⁺]. HRMS calcd for C₂₅H₃₇N₆O₆517.2775, found 517.2765.

(S)-2-Amino-3-(4-iodophenyl)propanoic acid (92)

To a solution (S)-2-amino-3-phenylpropanoic acid 91 (4.01 g, 24.3 mmol)in acetic acid (22 mL) was added sulfuric acid (2.9 mL, 5.14 mmol),iodine (2.47 g, 4.7 mmol) and sodium iodate (1.02 g, 5.14 mmol). Themixture was heated to 70° C. and allowed to stir at this temperature for16 h before an additional portion of sodium iodate (1.02 g, 5.14 mmol)was added. The reaction was left for a further 2 h before beingconcentrated, dissolved in methanol (20 mL) and treated with NaOH (60mL). The mixture was left to precipitate out of the basic solutionovernight and the resulting solid was filtered by vacuum filtration toyield the title compound (7.07 g, 24.3 mmol, 100%) as a pink solid,which had spectral data in agreement with that reported.⁹³ [α]_(D) ²¹−10.6 (c. 0.3, HCl). Mp 258-260° C. (lit. 261-262° C.)⁹³ ¹H NMR (CD₃OD,300 MHz): δ 7.71 (d, J=8.4 Hz, 2H, ArH2′ and ArH6′); 7.10 (d, J=8.4 Hz,2H, ArH3′ and ArH5′); 4.26 (dd, J=6.3, 7.2 Hz, H2); 3.26 (dd, J=5.4,14.1 Hz, 1H, H3_(a)); 3.04 (dd, J=7.2, 14.4 Hz, 1H, H3_(b)). MassSpectrum (CI, +ve) m/z 279 (100%), 292 (70%) [M⁺]. HRMS calcd forC₉H₁₁NO₂ 291.9834 found 291.9568.

Methyl(2S)-2-amino-3-(4-iodophenyl)propanoate hydrochloride (93)

To a solution of 92 (2.00 g, 6.87 mmol) in MeOH (10 mL) at 0° C. wasadded thionyl chloride (2 mL) and the resulting solution was allowed tostir for 16 h whilst equilibrating to RT. The reaction was evaporated todryness in vacuo to yield the title compound (2.25 g, 6.80 mmol, 99%) asa white solid, which had spectral data in agreement with thatreported.⁹³ [α]_(D) ²¹ −9.3 (c. 0.15, HCl). Mp 195-198° C. (lit.199.5-200.5° C.)⁹³ ¹H NMR (CD₃OD, 300 MHz): δ 7.72 (d, J=8.4 Hz, 2H,ArH2′ and ArH6′); 7.06 (d, J=8.4 Hz, 2H, ArH3′ and ArH5′); 4.33 (dd,J=6.3, 6.9 Hz, 1H, H2); 3.80 (s, 3H, OCH₃); 3.23 (dd, J=6.6, 14.4 Hz,1H, H3_(a)); 3.15 (dd, J=7.2, 14.4 Hz, 1H, H3_(b)). Mass Spectrum (ES,+ve) m/z 306 (100%) [M⁺]. HRMS calcd for C₁₀H₁₃INO₂ 305.9986 found305.9980.

Methyl(2S)-2-acetamido-3-(4-iodophenyl)propanoate (94)

To a solution of 93 (2.25 g, 6.80 mmol) in 10% HCl (10 mL) at 0° C. wasadded 4M sodium acetate (115 mL) and the resulting reaction was allowedto stir whilst equilibrating to 0° C. Acetic anhydride (50 mL) was addedand the reaction allowed to proceed with vigorous stirring. After 1 hthe product was collected by vacuum filtration, dissolved in ethylacetate (30 mL) and washed with 2M sodium bicarbonate (2×30 mL). Theorganic layer was dried and evaporated to yield the title compound (1.31g, 3.79 mmol, 56%) as a white solid. Mp 118-120° C. [α]_(D) ²⁷ +93.8 (c.0.1, CHCl₃). ¹H NMR (CDCl₃, 300 MHz): δ 7.61 (d, J=8.4 Hz, 2H, ArH2′ andArH6′); 6.84 (d, J=8.1 Hz, 2H, ArH3′ and ArH5′); 5.92 (d, J=7.2 Hz, 1H,NH); 4.87 (m, 1H, H2); 3.73 (s, 3H, OCH₃); 3.11 (dd, J=6.0, 13.8, Hz,1H, H3_(a)); 3.03 (dd, J=5.4, 13.8 Hz, 1H, H3_(b)); 1.99 (s, 3H,NCOCH₃). Mass Spectrum (CI, +ve) m/z 348 (100%) [MH⁺]. HRMS calcd forC₁₂H₁₅NO₃I 348.0097, found 348.0104.

Methyl(2S)-2-acetamido-3-(4-trimethylstannylphenyl)propanoate (95)

A solution of 94 (590 mg, 1.7 mmol), hexamethyldistannane (781 mg, 2.38mmol), palladium acetate (20 mg, 0.085 mmol), and triphenylphosphine (45mg, 0.17 mmol) in toluene (7 mL) was flushed with nitrogen for 15minutes and then heated at 100° C. for 30 min under N₂. The brownmixture was filtered through a short pad of silica, diluted with diethylether (40 mL) and washed twice with water. The organic layer was driedand evaporated to yield the title compound (497 mg, 1.29 mmol, 76%) as aclear oil. [α]_(D) ²⁷ +13.7 (c. 0.3, CHCl₃). ¹H NMR (CDCl₃, 300 MHz): δ7.41 (d, J=7.5 Hz, 2H, ArH2′ and ArH6′); 7.07 (d, J=7.8 Hz, 2H, ArH3′and ArH5′); 6.25 (d, J=7.8 Hz, 1H, NH); 4.87 (m, 1H H2); 3.72 (s, 3H,OCH₃); 3.12 (dd, J=5.7, 14.1 Hz, 1H, H3_(a)); 3.04 (dd, J=6.0, 13.9 Hz,1H, H3_(b)); 1.98 (s, 3H, NCOCH₃); 0.27 (t, J=27.6 Hz, 9H, Sn(CH₃)₃).Mass Spectrum (CI, +ve) m/z 386 (50%) [MH⁺], 382 (10%) [MH⁺] (Sn 112), δ(100%). HRMS calcd for C₁₅H₂₄NO₃Sn (Sn 112) 382.075357 found 382.075603.

Methyl(2S)-2-acetamido-3-(4-[9-anthracenyl]phenyl)-propanoate (96)

A solution of 95 (192 mg, 0.50 mmol), 9-bromoanthracene (141 mg, 0.55mmol), palladium acetate (6 mg, 0.025 mmol), and tri-o-tolylphosphine(15 mg, 0.05 mmol) in DMF (2 mL) was flushed with N₂ for 15 min thenheated to 70° C. and allowed to stir for 16 h. The reaction was dilutedwith diethyl ether (20 mL) and washed with water (5×20 mL), dried andevaporated. The crude product was purified by flash columnchromatography (15% EtOAc/hexane then 5% MeOH/DCM) to yield the titlecompound (133 mg, 0.33 mmol, 67%) as an orange oil. [α]_(D) ²⁷ +66.9 (c.0.1, CHCl₃). ¹H NMR (CDCl₃, 300 MHz): δ 8.48 (s, 1H, ArH10″); 8.03 (dd,J=0.9, 8.7 Hz, 2H, ArH3″ and ArH6″); 7.63 (dd, J=0.6, 9.0 Hz, 2H, ArH8″and ArH1″); 7.45 (m, 2H, ArH4″ and ArH5″); 7.36 (m, 6H, ArH2″ and ArH7″,4×ArH′); 5.40 (d, J=7.8 Hz, 1H, NH); 5.04 (m, 1H, H2); 3.79 (s, 3H,OCH₃); 3.32 (dd, J=5.7, 13.8 Hz, 1H, H3_(a)); 3.25 (dd, J=6.3, 13.8 Hz,1H, H3_(b)); 2.08 (s, 3H, COCH₃). Mass Spectrum (CI, +ve) m/z 398 (100%)[MH⁺]. HRMS calcd for C₂₆H₂₃NO₃ 397.1678, found 397.1675.

Methyl(2S)-2-acetamido-3-(4-[9-phenanthrenyl]phenyl)propanoate (98)

A solution of 95 (259 mg, 0.67 mmol), 9-bromophenanthrene (190 mg, 0.74mmol), palladium acetate (8 mg, 0.034 mmol), and tri-o-tolylphosphine(20 mg, 0.067 mmol) in DMF (2 mL) was flushed with N₂ for 15 min thenheated to 70° C. and allowed to stir for 16 h. The reaction was dilutedwith diethyl ether (20 mL) and washed with water (5×20 mL), dried andevaporated. The crude product was purified by flash columnchromatography (15% EtOAc/hexane then 5% MeOH/DCM) to yield the titlecompound (157 mg, 0.40 mmol, 59%) as a clear oil. [α]_(D) ²⁷ +94.6 (c.0.1, CHCl₃). ¹H NMR (CDCl₃, 300 MHz): δ 8.77 (d, J=9.0 Hz, 1H, ArH4″);8.71 (d, J=8.1 Hz, 1H, ArH3″); 7.89 (m, 2H, ArH1″ and ArH10″); 7.61 (m,5H, ArH7″, ArH6″, ArH5″, ArH2″ and ArH1″); 7.48 (d, J=8.4 Hz, 2H, ArH2′and ArH6′); 7.26 (d, J=8.1 Hz, 2H, ArH3′ and ArH5′); 6.25 (d, J=7.5 Hz,1H, NH); 5.00 (m, 1H, H2); 3.79 (s, 3H, OCH₃); 3.30 (dd, J=5.7, 13.8 Hz,1H, H3_(a)); 3.20 (dd, J=6.0, 13.8 Hz, 1H, H3_(b)); 2.05 (s, 3H, COCH₃).Mass Spectrum (CI, +ve) m/z 398 (100%) [MH⁺]. HRMS (EI) calcd forC₂₆H₂₃NO₃ 397.1678, found 397.1680.

(2S)-2-Acetamido-3-(4-[9-anthracenyl]phenyl) propanoic acid (97)

To a solution of 96 (80 mg, 0.02 mmol) in THF/water, 2:1 (3 mL) wasadded lithium hydroxide monohydrate (17 mg, 0.40 mmol) and the resultingsuspension was allowed to stir for 16 h. The reaction mixture wasdiluted with water (30 mL) and the THF was removed by evaporation. Theaqueous layer was washed with DCM (40 mL) to remove unreacted startingmaterial. The aqueous phase was acidified with 10% HCl and the resultingprecipitate was extracted with DCM (3×40 mL). The combined organics weredried and evaporated to yield the title compound (69 mg, 0.18 mmol, 90%)as a white solid. Mp 76° C. [α]_(D) ²⁰ +29.7 (c. 0.1, EtOH). ¹H NMR(CDCl₃, 300 MHz): δ 8.47 (s, 1H, ArH10″); 8.02 (d, J=8.4 Hz, 2H, ArH3″and ArH6″); 7.59 (d, J=8.7 Hz, 2H, ArH8″ and ArH1″); 7.45 (m, 2H, ArH4″and ArH5″); 7.35 (m, 6H, ArH2″ and ArH7″, 4×ArH′); 6.27 (d, J=6.6 Hz,1H, NH); 5.00 (m, 1H, H2); 3.39 (dd, J=4.8, 12.9 Hz, 1H, H3_(a)); 3.26(dd, J=6.3, 14.4 Hz, 1H, H3_(b)); 2.07 (s, 3H, COCH₃). Mass Spectrum(ES, +ve) m/z 383 (70%) [MH⁺]. HRMS calcd for C₂₅H₂₂NO₃ 384.1600, found384.1610.

(2S)-2-Acetamido-3-(4-[9-phenanthrenyl]phenyl)propanoic acid (99)

To a solution of 98 (124 mg, 0.31 mmol) in THF/water, 2:1 (9 mL) wasadded lithium hydroxide monohydrate (26 mg, 0.62 mmol) and the resultingsuspension was allowed to stir for 16 h. The reaction mixture wasdiluted with water (30 mL) and the THF was removed by evaporation. Theaqueous layer was washed with DCM (40 mL) to remove unreacted startingmaterial. The aqueous phase was acidified with 10% HCl and the resultingprecipitate was extracted with DCM (3×40 mL). The combined organics weredried and evaporated to yield the title compound (65 mg, 0.17 mmol, 55%)as a white solid. Mp 128-132° C. [α]_(D) ²⁰ +36.8 (c. 0.1, EtOH). ¹H NMR(CD₃OD, 300 MHz): δ 8.71 (d, J=8.1 Hz, 1H, ArH4″); 8.66 (d, J=8.4 Hz,1H, ArH3″); 7.79 (s, 1H, ArH1″); 7.76 (s, 1H, ArH10″); 7.51 (m, 5H,ArH7″, ArH6″, ArH5″, ArH2″ and ArH1″); 7.32 (m, 2H, Ar′H); 4.76 (dd,J=5.1, 9.0 Hz, 1H, H2); 3.29 (dd, J=4.8, 13.5 Hz, 1H, H3_(a)); 3.03 (dd,J=8.7, 13.5 Hz, 1H, H3_(b)); 1.95 (s, 3H, COCH₃). Mass Spectrum (ES,+ve) m/z 384 (50%) [MH⁺]. HRMS calcd for C₂₅H₂₂NO₃ 384.1600, found384.1628.

(2′-Allyloxy-[1,1′]-(S)-binaphthalen-2-yloxy)-acetic acid (101)

To a solution of 1,1′-(S)-binapthol (1.00 g, 3.50 mmol) and K₂CO₃ (600mg, 4.35 mmol) in acetone (12 mL) was added dropwise, allyl bromide(0.26 mL, 3.68 mmol). The resulting mixture was heated at reflux withstirring for 16 h before being filtered, concentrated and dissolved inanhydrous MeOH (40 mL). To this solution was added K₂CO₃ (2.4 g, 17.4mmol) and bromoacetic acid (1.21 g, 8.75 mmol). This mixture was heatedat reflux for a further 3 h before evaporation to dryness anddissolution in water (50 mL). The aqueous layer was then washed withdiethyl ether (3×30 mL) before acidification with 3M HCl. The acidifiedsolution was extracted with DCM, dried before being evaporated todryness to yield the title compound (825 mg, 2.15 mmol, 61%) as aviscous yellow oil. ¹H NMR (CDCl₃, 300 MHz): δ 7.96 (m, 2H, ArH); 7.86(m, 2H, ArH); 7.26 (m, 8H, ArH); 5.66 (m, 1H, H2″); 4.94 (m, 2H, H3″);4.61 (AB_(q), J=16.8 Hz, 2H, CH, —COOH); 4.48 (m, 2H, H1″). MassSpectrum (CI, +ve) m/z 339 (40%) [—COOH], 385 (100%) [MH⁺]. HRMS calcdfor C₂₅H₂₁O₄ 385.143984, found 385.142526.

(2′-Benzyloxy-[1,1′]-(S)-binaphthalen-2-yloxy)-acetic acid (102)

To a solution of 1,1′-(S)-binapthol (500 mg, 1.75 mmol) and K₂CO₃ (300mg, 2.18 mmol) in acetone (6 mL) was added dropwise, benzyl bromide(0.21 mL, 1.75 mmol). The resulting mixture was heated at reflux withstirring for 16 h before being filtered, concentrated and dissolved inanhydrous MeOH (5 mL). To this solution was added K₂CO₃ (2.4 g, 17.4mmol) and bromoacetic acid (740 g, 5.25 mmol). This mixture was heatedat reflux for a further 3 h before evaporation to dryness anddissolution in water (50 mL). The aqueous layer was then washed withdiethyl ether (3×30 mL) before acidification with 3M HCl. The acidifiedsolution was extracted with DCM, dried before being evaporated todryness to yield the title compound (218 mg, 0.50 mmol, 29%) as aviscous yellow oil. ¹H NMR (CDCl₃, 300 MHz): δ 10.30 (bs, 1H, COOH);7.85 (m, 4H, ArH); 7.16 (m, 13H, ArH); 4.99 (AB_(q), J=12.6 Hz, 2H, CH₂—COOH); 4.48 (AB_(q), J=17.1 Hz, 2H, H1″). Mass Spectrum (CI, +ve) m/z435 (100%) [MH⁺]. HRMS calcd for C₂₉H₂₃O₄ 435.159634, found 435.158151.

(2′-Methyloxy-[1,1′]-(S)-binaphthalen-2-yloxy)-acetic acid (103)

To a solution of 1,1′-(S)-binapthol (500 mg, 1.75 mmol) and K₂CO₃ (300mg, 2.18 mmol) in acetone (6 mL) was added dropwise, methyl iodide (0.11mL, 1.75 mmol). The resulting mixture was heated at reflux with stirringfor 16 h before being filtered, concentrated and dissolved in anhydrousMeOH (5 mL). To this solution was added K₂CO₃ (2.4 g, 17.4 mmol) andbromoacetic acid (740 g, 5.25 mmol). This mixture was heated at refluxfor a further 3 h before evaporation to dryness and dissolution in water(50 mL). The aqueous layer was then washed with diethyl ether (3×30 mL)before acidification with 3M HCl. The acidified solution was extractedwith DCM, and dried before being evaporated to dryness to yield thetitle compound (236 mg, 0.66 mmol, 38%) as a viscous yellow oil. ¹H NMR(CDCl₃, 300 MHz): δ 10.22, COOH; 7.84 (m, 4H, ArH); 7.22 (m, 8H, ArH);4.49 (AB_(q), J=16.8 Hz, 2H, CH ₂—COOH); 3.65 (s, 3H, OCH₃). MassSpectrum (CI, +ve) m/z 359 (100%) [MH⁺]. HRMS (EI) calcd for C₂₃H₁₈O₄358.120509, found 358.120418.

(2′-(3-Phenylallyloxy)-[1,1′]-(S)-binaphthalen-2-yloxy)-acetic acid(104)

To a solution of 1,1′-(S)-binapthol (500 mg, 1.75 mmol) and K₂CO₃ (300mg, 2.18 mmol) in acetone (6 mL) was added dropwise, cinnamyl bromide(362 mg, 1.84 mmol). The resulting mixture was heated at reflux withstirring for 16 h before being filtered, concentrated and dissolved inanhydrous MeOH (5 mL). To this solution was added K₂CO₃ (2.4 g, 17.4mmol) and bromoacetic acid (740 g, 5.25 mmol). This mixture was heatedat reflux for a further 3 h before evaporation to dryness anddissolution in water (50 mL). The aqueous layer was then washed withdiethyl ether (3×30 mL) before acidification with 3M HCl. The acidifiedsolution was extracted with DCM, dried, then evaporated to dryness toyield the title compound (544 mg, 1.18 mmol, 67%) as a viscous yellowoil. ¹H NMR (CDCl₃, 300 MHz): δ 10.20, COOH; 7.84 (m, 4H, ArH); 7.29 (m,4H, ArH); 7.09 (m, 8H, ArH); 6.12 (d, J=15.9 Hz, 1H, H3″); 5.90 (dt,J=5.7, 15.9 Hz, 1H, H2″); 5.58 (m, 2H, H1″); 4.49 (AB_(q), J=16.8 Hz,2H, CH ₂—COOH). Mass Spectrum (CI, +ve) m/z 117 (100%), 461 (50%) [MH⁺].HRMS calcd for C₃₁H₂₄O₄ 460.167460, found 460.167568.

[2′-(3-Methylbutoxy-[1,1′]-(S)-binaphthalen-2-yloxy]-acetic acid (105)

To a solution of 1,1′-(S)-binapthol (500 mg, 1.75 mmol) and K₂CO₃ (300mg, 2.18 mmol) in acetone (6 mL) was added dropwise,1-bromo-3-methylbutane (0.22 mL, 1.75 mmol). The resulting mixtureheated at reflux with stirring for 16 h before being filtered,concentrated and dissolved in anhydrous MeOH (5 mL). To this solutionwas added K₂CO₃ (2.4 g, 17.4 mmol) and bromoacetic acid (740 g, 5.25mmol). This mixture was heated at reflux for a further 3 h beforeevaporation to dryness and dissolution in water (50 mL). The aqueouslayer was then washed with diethyl ether (3×30 mL) before acidificationwith 3M HCl. The acidified solution was extracted with DCM, dried beforebeing evaporated to dryness to yield the title compound (604 mg, 1.46mmol, 83%) as a viscous yellow oil. ¹H NMR (CDCl₃, 300 MHz): δ 9.93,COOH; 7.95 (m, 4H, ArH); 7.40 (m, 8H, ArH); 4.65 (m, 2H, CH ₂—COOH);4.09 (m, 2H, H1″); 1.38 (m, 2H, H2″); 1.26 (m, 1H, H3″); 0.71 (d, J=6.3Hz, 3H, H4a″); 0.61 (d, J=6.3 Hz, 3H, H4b″). Mass Spectrum (CI, +ve) m/z415 (100%) [MH⁺]. HRMS calcd for C₂₇H₂₇O₄ 415.1090, found 415.1913.

(2′-(3-Phenylpropyloxy)-[1,1′]-(S)-binaphthalen-2-yloxy)-acetic acid(107)

To a solution 104 (213 mg, 0.46 mmol) in THF (15 mL) was added palladiumon activated carbon (5 mol %). The resulting mixture was allowed to stirfor 16 h under a hydrogen atmosphere (balloon) before being filtered andevaporated to dryness to yield the title compound (188 mg, 0.4 mmol,87%) as a viscous yellow oil. ¹H NMR (CDCl₃, 300 MHz): δ 7.97 (m, 4H,ArH); 7.24 (m, 11H, ArH); 6.68 (m, 2H, ArH); 4.65 (AB_(q), J=16.8 Hz,2H, CH ₂—COOH); 3.96 (m, 2H, H1″); 2.09 (m, 2H, H3″); 1.69 (m, 2H, H2″).Mass Spectrum (CI, +ve) m/z 463 (100%) [MH⁺]. HRMS calcd for C₃₁H₂₇O₄463.1909, found 463.1915.

Benzyl(2S)-2-amino-4-pentenoate hydrochloride (108)

To a solution of (2S)-2-amino-4-pentenoic acid 17 (225 mg, 1.96 mmol) inbenzyl alcohol (5 mL) was added thionyl chloride (2 mL) and theresulting mixture was allowed to stir for 16 h before addition ofdiethyl ether (30 mL) and extraction with water (3×30 mL). The aqueouslayer was concentrated, diluted with 2M sodium bicarbonate (20 mL), andextracted with DCM (3×30 mL). The combined organic fractions were driedand acidified with 1M HCl/diethyl ether (2 mL) and evaporated. The crudeproduct dissolved in a minimal volume of MeOH and precipitated withdiethyl ether to yield the title compound (322 mg, 1.34 mmol, 68%) as awhite solid. [α]_(D) ²⁰ −40.6 (c. 0.1, H₂O). Mp 186-191° C. ¹H NMR (D₂O,300 MHz): δ 7.28 (m, 5H, ArH); 5.51 (m, 1H, H4); 5.11 (m, 4H, H5 andArCH₂); 4.08 (t, J=5.4 Hz, 1H, H2); 2.55 (m, 2H, H3). Mass Spectrum (CI,+ve) m/z 205 (25%) [MH⁺]. HRMS calcd for C₁₂H₁₆NO₂ 206.1181, found206.1169.

Benzyl(2S,5R)-2-allyl-3-aza-5-(9H-9-fluorenylmethyloxycarboxamido)-4-oxo-8-[(2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl)guanidino]octanoate(109)

The title compound was synthesised using the general peptide couplingprocedure (Procedure B), from 108 (155 mg, 0.65 mmol) and(2R)-2-(9H-9-fluorenylmethyloxycarboxamido)-8-[(2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl)guanidine]pentanoicacid (431 mg, 0.65 mmol) to afford 109 (280 mg, 0.33 mmol, 51%) as awhite solid. Mp 78-74° C. ¹H NMR (CDCl₃, 300 MHz): δ 7.69 (d, J=7.5 Hz,2H, ArH1″ and ArH8″); 7.51 (d, J=7.5 Hz, 2H, ArH4″ and ArH5″); 7.28 (m,9H, ArH); 6.33 (m, 3H, NH); 5.68 (m, 1H, H2′); 5.61 (m, 1H, NH); 4.99(m, 4H, ArCH₂ and H3′); 4.58 (m, 1H, H2); 4.24 (m, 3H, OCH ₂—H9″ andH5); 4.05 (t, J=7.2 Hz, 1H, H9″); 3.20 (m, 2H, H8); 2.57 (s, 3H,7′″-CH₃); 2.54 (s, 3H, 5′″-CH₃); 2.52 (m, 4H, H3′″ and H1′); 2.05 (s,3H, 8′″-CH₃); 1.85 (m, 2H, H6); 1.69 (t, J=6.3 Hz, H4′″); 1.58 (m, 2H,H7); 1.22 (s, 6H, 2×2′″-CH₃). Mass Spectrum (ES, +ve) m/z 850 (100%)[MH⁺]. HRMS calcd for C₄₇H₅₆N₅O₈S 850.3850, found 850.3855.

Benzyl(2S,5R)-2-allyl-5-amino-3-aza-8-[(2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonamido)guanidino]-4-oxooctanoate(110)

The title compound was synthesized using the general N-Fmoc deprotectionprocedure (Procedure C), from 109 (278 mg, 0.33 mmol) to yield 110 (144mg, 0.23 mmole, 70%) as a cream semi-solid. Mp 66-68° C. ¹H NMR (CDCl₃,300 MHz): δ 7.85 (d, J=7.8 Hz, 1H, NH); 7.60 (d, J=7.8 Hz, 1H, NH); 7.32(m, 5H, ArH); 6.33 (m, 2H, NH₂); 5.63 (s, 1H, H2′); 5.14 (m, 4H, ArCH₂and H3′); 4.56 (m, 1H, H2); 3.40 (m, 1H, H5); 3.16 (m, 2H, H8); 3.09 (m,2H, H11′); 2.61 (t, J=6.9 Hz, 2H, H4″); 2.56 (s, 3H, 7″-CH₃); 2.55 (s,3H, 5″-CH₃); 2.09 (s, 3H, 8″-CH₃); 1.78 (t, J=7.2 Hz, 2H, H3″); 1.68 (m,4H, H6 and NH₂); 1.54 (m, 2H, H7); 1.29 (s, 6H, 2×2″-CH₃). Mass Spectrum(ES, +ve) m/z 628 (100%) [MH⁺]. HRMS calcd for C₃₂H₄₆N₅O₆S 628.3169,found 628.3157.

Benzyl(2S,5R,8R)-2-allyl-3,6-diaza-12-(tert-butoxycarboxamido)-8-(9H-9-fluorenylmethyloxycarboxamido)-5-([{2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonamido}guanidino]propyl)-4,7-dioxododecanoate(111)

The title compound was synthesised using the general peptide couplingprocedure (Procedure B), from 110 (200 mg, 0.32 mmol) and(2R)-6-tert-butoxycarboxamido-2-(9H-9-fluorenylmethyloxycarboxamido)hexanoicacid (151 mg, 0.32 mmol) to afford 111 (202 mg, 0.19 mmol, 59%) as awhite solid. Mp 116° C. ¹H NMR (CDCl₃, 300 MHz): δ 7.72 (d, J=7.8 Hz,2H, ArH1″″ and ArH8″″); 7.55 (d, J=7.8 Hz, 2H, ArH4″″ and ArH5″″); 7.45(m, 1H, NH); 7.29 (m, 1H, ArH); 6.25 (m, 3H, NH); 5.64 (m, 1H, H2′);5.03 (m, 4H, ArCH₂, H3′); 4.59 (m, 1H, H2); 4.51 (m, 1H, H5); 4.29 (m,1H, H8); 4.20 (m, 2H, OCH ₂—H9″″); 3.98 (m, 1H, H19″″); 3.18 (m, 2H,H3″); 3.05 (m, 2H, H12); 2.55 (s, 3H, 7′″-CH₃); 2.52 (s, 3H, 5′″-CH₃);2.50 (m, 4H, H4′″ and H1′); 2.03 (s, 3H, 8′″-CH₃); 1.95 (m, 4H, H1″ andH9); 1.74 (m, 2H, H13′″); 1.67 (m, 4H, H2″ and H10); 1.59 (m, 2H, H11);1.41 (s, 6H, 2×2′″-CH₃). Mass Spectrum (ES, +ve) m/z 1078 (10%) [MH⁺];288 (100%). HRMS calcd for C₅₈H₇₆N₇O₁₁S 1078.5324, found 1078.5333.

Benzyl(2S,5R,8R)-2-allyl-8-amino-3,6-diaza-12-(tert-butoxycarboxamido)-5-([{2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonamido}guanidino]propyl)-4,7-dioxododecanoate(112)

The title compound was synthesized using the general N-Fmoc deprotectionprocedure (Procedure C), from 111 (202 mg, 0.19 mmol) to yield 112 (157mg, 0.18 mmole, 93%) as a cream oil. ¹H NMR (CDCl₃, 300 MHz): δ 8.00 (d,J=7.2 Hz, 1H, NH); 7.58 (d, J=7.2 Hz, 1H, NH); 7.32 (m, 5H, ArH); 6.44(m, 3H, NH); 5.63 (m, 1H, H2′); 5.09 (m, 4H, ArCH₂ and H3′); 4.61 (m,2H, H2 and H5); 3.36 (m, 1H, H8); 3.22 (m, 2H, H3″); 3.05 (m, 2H, H12);2.62 (m, 2H, H4′″); 2.58 (s, 3H, 7′″-CH₃); 2.56 (s, 3H, 5′″-CH₃); 2.47(m, 2H, H1′); 2.15 (m, 2H, H1″); 2.10 (s, 3H, 8′″-CH₃); 1.89 (m, 2H,H9); 1.80 (t, J=6.3 Hz, H13′″); 1.72 (m, 4H, H2″ and H10); 1.58 (m, 4H,H₁₁ and NH₂); 1.42 (s, 9H, C(CH₃)₃); 1.31 (s, 6H, 2×2′″-CH₃). MassSpectrum (ES, +ve) m/z 856 (100%) [MH⁺]. HRMS calcd for C₄₃H₆₆N₇O₉S856.4643, found 856.4655.

Methyl(2S,5R)-2-(4-allyloxybenzyl)-5-amino-3-aza-8-[(2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl)guanidino]-4-oxononanoate(113)

The title compound was synthesized using the general N-Fmoc deprotectionprocedure (Procedure C), from 67 (295 mg, 0.32 mmol) to yield 113 (145mg, 0.21 mmol, 66%) as a cream oil. ¹H NMR (CDCl₃, 300 MHz): δ 7.83 (d,J=7.5 Hz, 1H, NH); 7.04 (d, J=8.4 Hz, 2H, ArH2′ and ArH6′); 6.81 (d,J=8.4 Hz, 2H, ArH3′ and ArH5′); 6.37 (bs, 2H, NH); 6.01 (m, 1H, H2″);5.30 (m, 2H, H3″); 4.68 (dd, J=7.5, 13.2 Hz, 1H, H2); 4.47 (m, 2H, H1″);4.22 (m, 1H, H5); 3.67 (s, 3H, OCH₃); 3.07 (m, 4H, H8 and ArCH₂); 2.61(t, J=6.6 Hz, 2H, H14′″); 2.56 (s, 3H, 7′″-CH₃); 2.54 (s, 3H, 5′″-CH₃);2.10 (s, 3H, 8′″-CH₃); 1.87 (m, 2H, NH₂); 1.79 (m, 2H, H13′″); 1.68 (m,2H, H6); 1.50 (m, 2H, H7); 1.29 (s, 6H, 2×2′″-CH₃). Mass Spectrum (ES,+ve) m/z 658 (100%) [MH⁺]. HRMS calcd for C₃₃H₄₈N₅O₂S 658.3274 found658.3282.

Methyl(2S,5S,8S)-2-allyl-8-(4-[9-anthrecenyl]benzyl)-3,6,9-triaza-5-(4-[tert-butoxycarboxamido]butyl)-4,7,10-trioxoundecanoate(114)

The title compound was synthesised using the general peptide couplingprocedure (Procedure B), from 24 (35 mg, 0.098 mmol) and 97 (20 mg,0.052 mmol) to afford the title compound (22 mg, 0.030 mmol, 59%) as acream solid. Mp 128° C. ¹H NMR (CDCl₃, 300 MHz): δ 8.49 (s, 1H,ArH10″″); 8.04 (d, J=8.7 Hz, 2H, ArH2′″ and ArH6′″); 7.64 (d, J=8.4 Hz,2H, ArH3′″ and ArH5′″); 7.38 (m, 8H, ArH″″); 6.72 (d, J=7.2 Hz, 1H, NH);6.48 (d, J=7.2 Hz, 1H, NH); 6.37 (bs, 1H, NH); 5.59 (m, 1H, H2′); 5.06(m, 2H, H3′); 4.82 (m, 1H, H8); 4.60 (dd, J=6.9, 14.1 Hz, 1H, H2); 4.45(m, 1H, H5); 3.73 (s, 3H, OCH₃); 3.24 (m, 2H, ArCH₂); 3.08 (m, 2H, H4″);2.47 (m, 2H, H1′); 2.07 (s, 3H, H11); 1.93 (m, 2H, H1″); 1.68 (m, 2H,H3″); 1.50 (m, 2H, H2″); 1.44 (s, 9H, C(CH₃)₃). Mass Spectrum (ES, +ve)m/z 745 (50%) [MNa⁺], 723 (20%) [MH⁺], 623 (100%) [M less Boc]. HRMScalcd for C4A₄₉N₄O₇ 745.3601, found 745.3590.

Methyl(2S,5S,8S)-2-allyl-3,6,9-triaza-5-(4-[tert-butoxycarboxamido]butyl)-4,7,10-trioxo-8-(4-[9-phenanthrenyl]benzyl)undecanoate(115)

The title compound was synthesised using the general peptide couplingprocedure (Procedure B), from 24 (28 mg, 0.078 mmol) and 99 (15 mg,0.039 mmol) to afford 115 (14 mg, 0.019 mmol, 50%) as a cream solid. Mp132-134° C. ¹H NMR (CDCl₃, 300 MHz): δ 8.76 (d, J=8.1 Hz, 1H, ArH4″″);8.71 (d, J=8.4 Hz, 1H, ArH3″″); 7.88 (m, 2H, ArH1″″ and ArH10″″); 7.60(m, 5H, ArH7″″, ArH6″″, ArH5″″, ArH2″″ and ArH1″″); 7.45 (d, J=7.8 Hz,2H, ArH2′″ and ArH6′″); 7.33 (d, J=7.8 Hz, 2H, ArH3′″ and ArH5′″); 7.10(d, J=8.4 Hz, 1H, NH); 6.94 (d, J=8.7 Hz, 1H, NH); 6.74 (d, J=8.1 Hz,1H, NH); 5.61 (m, 1H, H2′); 5.06 (m, 2H, H3′); 4.90 (m, 1H, H8); 4.57(m, 2H, H2 and H5); 3.72 (s, 3H, OCH₃); 3.20 (m, 2H, ArCH₂); 3.08 (m,2H, H4″); 2.47 (m, 2H, H1′); 2.04 (s, 3H, H11); 1.92 (m, 2H, H1″); 1.68(m, 2H, H3″); 1.48 (m, 2H, H2″); 1.42 (s, 9H, C(CH₃)₃). Mass Spectrum(ES, +ve) m/z 745 (60%) [MNa⁺], 723 (20%) [MH⁺], 623 (100%) [M lessBoc]. HRMS calcd for C₄₂H₅₁N₄O₇ 723.3758, found 723.3767.

Methyl(2S,5R)-2-allyloxybenzyl-8-(2-[2′-allyloxy-{1,1′}-(S)-binaphthalen-2-yloxy])-3,6-diaza-5-([{2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl}guanidino]propyl)-4,7-dioxooctanoate(116)

The title compound was synthesised using the general peptide couplingprocedure (Procedure B), from 113 (81 mg, 0.11 mmol) and 101 (49 mg,0.13 mmol) to afford 116 (70 mg, 0.065 mmol, 59%) as a white solid. Mp110° C. ¹H NMR (CDCl₃, 300 MHz): δ 7.88 (m, 4H, ArH); 7.75 (d, J=8.4 Hz,1H, NH); 7.22, (m, 8H, ArH); 6.99 (d, J=8.7 Hz, 2H, ArH2′ and ArH6′);6.79 (d, J=8.7 Hz, 2H, ArH3′ and ArH5′); 6.31 (d, J=8.1 Hz, 1H, NH);6.15 (bs, 2H, NH); 5.98 (m, 1H, H2″); 5.77 (bs, 1H, NM; 5.63 (m, 1H,H2′″″); 5.35 (dd, J=1.5, 18.9 Hz, 1H, H3_(a)″); 5.23 (dd, J=1.5, 10.5Hz, 1H, H3b″); 4.88 (m, 2H, H3′″″); 4.64 (m, 1H, H2); 4.40 (m, 6H, H1″,H1′″″ and H8); 4.13 (m, 1H, H5); 3.61 (s, 3H, OCH₃); 2.91 (m, 4H, ArCH₂and H3′″); 2.60 (s, 3H, 7″″-CH₃); 2.78 (s, 3H, 5″″-CH₃); 2.54 (m, 2H,H4″″); 2.10 (s, 3H, 8″″-CH₃); 1.75 (t, J=6.6 Hz, 2H, H3″″); 1.36 (m, 2H,H2′″); 1.26 (s, 6H, 2×2″″-CH₃); 0.84 (m, 2H, H1′″). Mass Spectrum (ES,+ve) 7m/z 1024 (100%) [MH⁺]. HRMS calcd for C₅₈H₆₆N₅O₁₀S 1024.4530,found 1024.4513.

Methyl(2S,5R)-2-allyloxybenzyl-3,6-diaza-5-([{2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl}guanidino]propyl)-4,7-dioxo-8-(2-[2′-{3-phenyl-allyloxy}-{1,1′}-(S)-binaphthalen-2-yloxy])octanoate(117)

The title compound was synthesised using the general peptide couplingprocedure (Procedure B), from 113 (64 mg, 0.09 mmol) and 104 (42 mg,0.09 mmol) to afford 117 (61 mg, 0.055 mmol, 62%) as a cream solid. Mp100° C. ¹H NMR (CDCl₃, 300 MHz): δ 7.90 (m, 4H, ArH); 7.76 (d, J=8.1 Hz,1H, NH); 7.46 (d, J=9.0 Hz, 1H, NH); 7.17, (m, 13H, ArH); 6.99 (d, J=8.4Hz, 2H, ArH2′ and ArH6′); 6.79 (d, J=8.4 Hz, 2H, ArH3′ and ArH5′); 6.39(d, J=8.1 Hz, 1H, NH); 6.13 (m, 2H, H2′″″ and H3′″″); 5.98 (m, 1H, H2″);5.30 (m, 2H, H3″); 4.64 (m, 1H, H2); 4.39 (m, 6H, H1″, H1′″″ and H8);4.15 (m, 1H, H5); 3.60 (s, 3H, OCH₃); 2.95 (m, 4H, ArCH₂ and H13′″);2.60 (s, 3H, 7″″-CH₃); 2.58 (s, 3H, 5″″-CH₃); 2.52 (m, 2H, H4″″); 2.10(s, 3H, 8″″-CH₃); 1.74 (t, J=6.7 Hz, 2H, H3″″); 1.36 (m, 2H, H12′″);1.25 (s, 6H, 2×2″″-CH₃); 0.85 (m, 2H, H1′″). Mass Spectrum (ES, +ve) m/z1100 (100%) [MH⁺]. HRMS calcd for C₆₄H₇₀N₅O₁₀S 1100.4843, found1100.4833.

Methyl(2S,5S,8S)-2-allyl-5-(4-aminobutyl)-8-(4-[9-anthrecenyl]benzyl)-3,6,9-triaza-5-butylamino-4,7,10-trioxoundecanoatehydrochloride (118)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 114 (20 mg, 0.028 mmol) to yield 118 (13mg, 0.017 mmol, 61%) as a light yellow solid. Mp 194-202° C. ¹H NMR(CD₃OD, 300 MHz): δ 8.53 (s, 1H, ArH10″″); 8.26 (m, 3H, exchangingNH's); 8.06 (d, J=8.1 Hz, 2H, ArH2′″ and ArH6′″); 7.64 (d, J=9.0 Hz, 2H,ArH3′″ and ArH5′″); 7.38 (m, 8H, ArH″″); 5.68 (m, 1H, H2′); 5.02 (m, 2H,H3′); 4.67 (m, 1H, H8); 4.45 (m, 2H, H2 and H5); 3.69 (s, 3H, OCH₃);2.93 (m, 4H, H4″ and ArCH₂); 2.44 (m, 2H, H1′); 2.00 (s, 3H, H11); 1.69(m, 4H, H1″ and H3″); 1.50 (m, 2H, H2″). ¹³C NMR (CD₃OD, 75 MHz): δ174.4, C7; 173.7, C1; 173.6, C4; 173.5, C10; 138.7, ArC4′″; 137.8,ArC1′″; 137.7, ArC9″″; 134.1, C2′; 132.9, ArCH2′″ and ArCH6′″; 132.4,ArC4a″″ and ArC10a″″; 131.5, ArC8a″″ and ArC9a″″; 130.4, ArCH4″″ andArCH5″″; 130.1, ArCH3′″ and ArCH5′″; 129.5, ArCH10″″; 127.7, ArCH8″″ andArCH1″″; 126.5, ArCH2″″ and ArCH7″″; 126.2, ArCH3″″ and ArCH6″″; 118.8,C3′; 56.7, C5; 53.8, OCH₃; 53.6, C8; 52.7, C2; 40.5, C4″; 38.6, ArCH₂;36.6, C1′; 32.8, C1″; 28.1, C3″; 23.4, C11; 22.4, C2″. Mass Spectrum(ES, +ve) m/z 623 (100%) [M⁺]. HRMS calcd for C₃₇H₄₃N₄O₅ 623.3233, found623.3215.

Methyl(2S,5S,8S)-2-allyl-5-(4-aminobutyl)-3,6,9-triaza-5-butylamino-4,7,10-trioxo-8-(4-[9-[phenanthrenyl]benzyl)undecanoatehydrochloride (119)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 115 (24 mg, 0.033 mmol) to yield 119 (15mg, 0.023 mmol, 69%) as a light yellow solid. Mp 198° C. ¹H NMR (CD₃OD,300 MHz): δ 8.84 (d, J=7.8 Hz, 1H, ArH4″″); 8.78 (d, J=8.1 Hz, 1H,ArH5″″); 8.30 (d, J=7.2 Hz, 1H, exchanging NH); 8.15 (d, J=8.1 Hz, 1H,exchanging NH); 7.90 (m, 2H, ArH1″″ and ArH10″″); 7.60 (m, 5H, ArH7″″,ArH6″″, ArH15″″, ArH2″″ and ArH1″″); 7.45 (d, J=8.4 Hz, 2H, ArH2′″ andArH6′″); 7.40 (d, J=8.7 Hz, 2H, ArH3′″ and ArH5′″); 5.68 (m, 1H, H2′);4.98 (m, 2H, H3′); 4.61 (m, 1H, H8); 4.40 (m, 2H, H2 and H5); 3.67 (s,3H, OCH₃); 2.93 (t, J=7.5 Hz, 2H, H4″); 2.40 (m, 2H, H1′); 1.99 (s, 3H,H111); 1.83 (m, 4H, H1″ and ArCH₂); 1.69 (m, 2H, H3″); 1.49 (m, 2H,H2″). ¹³C NMR (CD₃OD, 75 MHz): δ 173.7, C7; 173.6, C1; 173.5, C4; 173.4,C10; 140.7, ArC4′″; 139.8, ArC1′″; 137.5, ArC9″″; 134.0, C2′; 133.0,ArC8a″″; 132.3, ArC4b″″; 132.0, ArC4a″″; 131.3, ArCH2′″ and ArCH6′″;131.2, ArC10a″″; 130.3, ArCH3′″ and ArCH5′″; 129.7, ArCH1″″; 128.5,ArCH7″″; 128.0, ArCH6″″; 127.9, ArCH1 ″″; 127.8, ArCH5″″; 127.7,ArCH10″″; 127.6, ArCH2″″; 124.2, ArC4″″; 124.1, ArCH3″″; 118.8, C3′;56.7, C5; 53.7, OCH₃; 53.6, C8; 52.7, C2; 40.5, C4″; 38.5, ArCH₂; 36.5,C1′; 32.8, C1″; 28.0, C3″; 23.3, C11; 22.4, C2″. Mass Spectrum (ES, +ve)m/z 623 (100%) [M⁺]. HRMS calcd for C₃₇H₄₃N₄O₅ 623.3233, found 623.3262.

Methyl(2S,5R)-2-allyloxybenzyl-8-(2-[2′-allyloxy-{1,1′}-(S)-binaphthalen-2-yloxy])-3,6-diaza-5-(3-[guanidino)-4,7-dioxooctanoatehydrochloride (120)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A) using 116 (70 mg, 0.068 mmol) to yield 120 (31mg, 0.039 mmol, 58%) as a cream solid. Mp 104-110° C. ¹H NMR (CD₃OD, 500MHz): δ 7.62 (m, 4H, ArH); 6.95, (m, 8H, ArH); 6.82 (d, J=7.0 Hz, 2H,ArH2′ and ArH6′); 6.58 (d, J=7.0 Hz, 2H, ArH3′ and ArH5′; 5.74 (m, 1H,H2″); 5.40 (m, 1H, H12′″″); 5.09 (d, J=17.0 Hz, 1H, H3_(a)″); 4.93 (d,J=10.0 Hz, 1H, H3b″); 4.62 (m, 2H, H3′″″); 4.37 (m, 1H, H2); 4.18 (m,6H, H1″, H1′″″ and H8); 3.98 (m, 1H, H5); 3.36 (s, 3H, OCH₃); 2.75 (m,4H, ArCH₂ and H13′″; 1.40 (m, 2H, H1′″); 0.68 (m, 2H, H2″″). ¹³C NMR(CD₃OD, 125 MHz): δ 173.1, C1; 172.3, C7; 170.5, C4; 158.8, CN₃; 158.2,ArC; 155.1, ArC; 153.8, ArC; 134.9, ArC4′; 134.8, ArC; 134.7, C2″;134.7, C2′″″; 131.3, ArCH; 131.2, ArCH; 130.8, ArCH; 130.7, ArCH; 130.5,ArCH2′ and ArCH6′; 130.0, ArCH; 129.1, ArCH; 129.1, ArC; 129.1, ArC;127.5, ArCH; 127.4, ArCH; 126.4, ArC1′; 125.7, ArCH; 125.2, ArCH; 124.8,ArC; 121.6, ArCH; 120.1, ArCH; 117.5, C3″; 117.0, C3′″″; 116.1, ArC;115.6, ArCH3′ and ArCH5′; 70.7, C8; 69.6, C1″; 69.2, C1′″″; 55.0, C2;52.8, OCH₃; 52.6, C5; 41.6, C3′″; 37.4, ArCH₂; 30.4, C1′″; 25.6, C2′″.Mass Spectrum (ES, +ve) m/z 758 (100%) [M⁺]. HRMS calcd for C₄₄A₄₉N₅O₇759.3632, found 759.3555.

Methyl(2S,5R)-2-allyloxybenzyl-3,6-diaza-8-(2-[2′-hydroxy-{1,1′}-(S)-binaphthalen-2-yloxy])-5-(3-[guanidino]propyl)-4,7-dioxooctanoate(121)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A) using 117 (58 mg, 0.053 mmol) to yield 121 (28mg, 0.037 mmol, 70%) as a cream solid. Mp 132° C. ¹H NMR (CD₃OD, 500MHz): δ 7.91 (m, 4H, ArH); 7.20, (m, 8H, ArH); 7.06 (d, J=8.4 Hz, 2H,ArH2′ and ArH6′); 6.83 (d, J=8.4 Hz, 2H, ArH3′ and ArH5′); 6.01 (m, 1H,H2″); 5.29 (m, 2H, H3″); 4.62 (m, 2H, H8); 4.55 (dd, J=4.5, 9.6 Hz, 1H,H2); 4.46 (m, 2H, H1″); 4.22 (dd, J=5.4, 8.7 Hz, 1H, H5); 3.67 (s, 3H,OCH₃); 3.00 (m, 4H, ArCH₂ and H3′″); 1.58 (m, 2H, H1′″); 1.06 (m, 2H,H12′″). ¹³C NMR (CD₃OD, 125 MHz): δ 173.2, C1; 172.7, C7; 171.0, C4;159.5, CN₃; 159.1, ArC; 158.4, ArC; 153.7, ArC4′; 135.4, ArC; 135.3,ArC; 134.9, C2″; 132.5, ArCH; 131.5, ArCH; 131.4, ArCH; 131.2, ArCH;130.6, ArCH2′ and ArCH6′; 130.3, ArCH; 130.1, ArCH; 129.2, ArCH; 128.2,ArCH; 127.7, ArCH; 127.4, ArCH; 126.4, ArC1′; 125.3, ArC; 124.1, ArC;121.1, ArC; 119.6, ArC; 117.5, C3″; 116.7, ArCH; 115.9, ArCH; 115.8,ArCH3′ and ArCH5′; 69.7, C8; 69.0, C1″; 55.2, C2; 53.1, OCH₃; 52.8, C5;42.0, C3′″; 37.4, ArCH₂; 30.1, C1′″; 25.5, C2′″. Mass Spectrum (ES, +ve)m/z 718 (100%) [M⁺]. HRMS calcd for C₄₁H₄₄N₅O₇ 718.3241, found 718.3209.

Benzyl(2S,5R,8R)-2-allyl-1-(2-[2′-allyloxy-{1,1′}-(S)-binaphthalen-2-yloxy])-3,6,9-triaza-8-(tert-butoxycarboxamidobutyl)-5-(3-[{2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl}guanidino]propyl)-4,7,10-trioxoundecanoate(122)

The title compound was synthesised using the general peptide couplingprocedure (Procedure B), from 112 (63 mg, 0.073 mmol) and 101 (28 mg,0.073 mmol) to afford 122 (71 mg, 0.058 mmol, 79%) as a white solid. Mp72-74° C. ¹H NMR (CDCl₃, 300 MHz): δ 7.93 (m, 2H, ArH); 7.85 (m, 2H,ArH); 7.27 (m, 13H, ArH); 6.20 (m, 2H, NH); 5.63 (m, 2H, H2′ and H2′″″);5.13 (AB_(q), J=12.3 Hz, 2H, PhCH ₂O); 4.94 (m, 6H, H11, H3′ and H3′″″);4.50 (m, 4H, H1′″″, H2 and H5); 4.06 (m, 1H, H8); 3.08 (m, 2H, H3″);2.89 (m, 2H, H4″″); 2.57 (m, 2H, H4′″); 2.55 (s, 3H, 7′″-CH₃); 2.53 (s,3H, 5′″-CH₃); 2.49 (m, 2H, H1′); 2.08 (s, 3H, 8′″-CH₃); 1.75 (t, J=6.3Hz, H3′″); 1.52 (m, 2H, H1″); 1.40 (s, 9H, C(CH₃)₃); 1.34 (m, 2H, H1″″);1.27 (s, 6H, 2×2′″-CH₃); 1.21 (m, 2H, H3″″); 0.95 (m, 2H, H2″); 0.77 (m,2H, H2″″). Mass Spectrum (ES, +ve) m/z 1222 (10%) [M], 1172 (100%). HRMScalcd for C₆₈H₈₄N₇O₁₂S 1222.5899, found 1222.5889.

Benzyl(2S,5R,8R,11S)-2-allyl-11-(4-allyloxybenzyl)-3,6,9,12-tetraaza-8-(4-[tert-butoxycarboxamido]butyl)-5-([{2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonamido}guanidino]propyl)-4,7,10,13-tetraoxotetradecanoate(123)

The title compound was synthesised using the general peptide couplingprocedure (Procedure B), from 112 (60 mg, 0.069 mmol) and 16 (18 mg,0.068 mmol) to afford the 123 (65 mg, 0.058 mmol, 85%) as a white solid.Mp 94-102° C. ¹H NMR (CDCl₃, 300 MHz): δ 7.76 (bs, 1H, NH); 7.54 (bs,1H, NH); 7.41 (bs, 1H, NH); 7.31 (m, 5H, ArH); 7.09 (d, J=8.7 Hz, 2H,ArH2′″″ and ArH6′″″); 6.77 (d, J=8.4 Hz, 2H, ArH3′″″ and ArH5′″″); 6.39(bs, 3H, 3×NH's); 6.02 (m, 1H, H2″″″); 5.70 (m, 1H, H2′); 5.39 (dd,J=1.5, 17.1 Hz, 1H, H3_(a)″″″); 5.26 (dd, J=1.2, 10.5 Hz, 1H,H3_(b)″″″); 5.06 (m, 2H, H3′); 5.05 (m, 2H, PhCH ₂O); 4.65 (dd, J=6.9,13.5 Hz, 1H, H11); 4.57 (dd, J=8.1, 13.5 Hz, 1H, H2); 4.50 (m, 1H, H5);4.45 (d, J=5.4 Hz, 2H, H1″″″); 4.41 (m, 1H, H8); 4.14 (bs, 1H, NH); 3.15(m, 2H, H3″); 2.92 (m, 4H, H4″″ and 11-CH₂); 2.58 (m, 4H, H1′ and H4′″);2.53 (s, 3H, 7′″-CH₃); 2.52 (s, 3H, 5′″-CH₃); 2.08 (s, 3H, H14); 1.94(m, 4H, H1″ and H1″″); 1.84 (s, 3H, 8′″-CH₃); 1.78 (m, 2H, H3′″); 1.69(m, 4H, H2″ and H2″″); 1.55 (m, 2H, H3″″); 1.40 (s, 9H, C(CH₃)₃); 1.30(s, 6H, 2×2′″-CH₃). Mass Spectrum (ES, +ve) m/z 1101 (30%) [MH⁺]; 288(100%). HRMS calcd for C₅₇H₈₁N₈O₁₂S 1101.5695, found 1101.5731.

Benzyl(2S,5R,8R)-2-allyl-3,6,9-triaza-11-(2-[2′-benzyloxy-{1,1′}-(S)-binaphthalen-2-yloxy])-8-(tert-butoxycarboxamidobutyl)-5-(3-[{2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl}guanidino]propyl)-4,7,10-trioxoundecanoate(124)

The title compound was synthesised using the general peptide couplingprocedure (Procedure B), from 112 (58 mg, 0.067 mmol) and 102 (29 mg,0.067 mmol) to afford 124 (61 mg, 0.048 mmol, 71%) as a white solid. Mp114-119° C. ¹H NMR (CDCl₃, 300 MHz): δ 7.90 (m, 4H, ArH); 7.26 (m, 18H,ArH); 6.80 (d, J=6.9 Hz, 1H, NH); 6.23 (m, 3H, NH); 5.65 (m, 1H, H2′);5.07 (m, 6H, H11, PhCH ₂O-ester and H3′); 4.81 (m, 1H, H2); 4.60 (m, 1H,H5); 4.40 (m, 2H, H11); 4.08 (m, 1H, H8); 3.01 (m, 2H, H3″); 2.89 (m,2H, H4″″); 2.59 (m, 2H, H4′″); 2.57 (s, 3H, 7′″-CH₃); 2.54 (s, 3H,5′″-CH₃); 2.50 (m, 2H, H1′); 2.08 (s, 3H, 8′″-CH₃); 1.75 (t, J=6.6 Hz,H3′″); 1.52 (m, 2H, H1″); 1.41 (s, 9H, C(CH₃)₃); 1.35 (m, 2H, H1″″ andH3″″); 1.27 (s, 6H, 2×2′″-CH₃); 1.15 (m, 4H, H2″ and H2″″). MassSpectrum (ES, +ve) m/z 1272 (100%) [MH⁺]. HRMS calcd for C₇₂H₈₆N₇O₁₂S1272.6055, found 1272.6061.

Benzyl(2S,5R,8R)-2-allyl-3,6,9-triaza-8-(tert-butoxycarboxamidobutyl)-11-(2-[2′-methoxy-{1,1′}-(S)-binaphthalen-2-yloxy])-5-(3-[{2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl}guanidino]propyl)-4,7,10-trioxoundecanoate(125)

The title compound was synthesised using the general peptide couplingprocedure (Procedure B), from 112 (55 mg, 0.064 mmol) and 103 (23 mg,0.064 mmol) to afford 125 (51 mg, 0.042 mmol, 66%) as a white solid. Mp104° C. ¹H NMR (CDCl₃, 300 MHz): δ 7.91 (m, 4H, ArH); 7.30 (m, 13H,ArH); 6.23 (m, 3H, NH); 5.63 (m, 1H, H2′); 5.10 (m, 4H, PhCH ₂O andH3′); 4.80 (m, 1H, H2); 4.58 (m, 2H, H111); 4.41 (m, 1H, H5); 4.11 (m,1H, H8); 3.71 (s, 3H, OCH₃); 3.09 (m, 2H, H3″); 2.89 (m, 2H, H4″″); 2.56(m, 2H, H4′″); 2.54 (s, 3H, 7′″-CH₃); 2.51 (s, 3H, 5′″-CH₃); 2.48 (m,2H, H1′); 2.07 (s, 3H, 8′″-CH₃); 1.86 (m, 2H, H1″); 1.75 (t, J=5.7 Hz,H3′″); 1.56 (m, 2H, H1″″); 1.41 (s, 9H, C(CH₃)₃); 1.34 (m, 4H, H1″″ andH3″″); 1.27 (s, 6H, 2×2′″-CH₃); 1.54 (m, 4H, H2″ and H2″″). MassSpectrum (ES, +ve) m/z 1196 (30%) [MH⁺], 346 (100%). HRMS calcd forC₆₆H₈₂N₇O₁₂S 1196.5742, found 1196.5757.

Benzyl(2S,5R,8R)-2-allyl-3,6,9-triaza-8-(tert-butoxycarboxamidobutyl)-5-(3-[{2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl}guanidino]propyl)-11-(2-[2′-{3-phenylallyloxy}-[1,1′]-(S)-binaphthalen-2-yloxy])-4,7,10-trioxoundecanoate(126)

The title compound was synthesised using the general peptide couplingprocedure (Procedure B), from 112 (63 mg, 0.073 mmol) and 104 (34 mg,0.073 mmol) to afford 126 (64 mg, 0.049 mmol, 67%) as a white solid. Mp110-112° C. ¹H NMR (CDCl₃, 300 MHz): δ 7.91 (m, 4H, ArH); 7.28 (m, 18H,ArH); 6.22 (m, 3H, NH); 6.11 (d, J=16.2 Hz, 1H, H3′″″); 5.91 (dt, J=5.1,16.2 Hz, 1H, H2′″″); 5.64 (m, 1H, H2′); 5.10 (m, 6H, PhCH ₂O, H1′″″ andH3′); 4.81 (m, 1H, H2); 4.67 (m, 2H, H11); 4.59 (dd, J=7.5, 12.9 Hz, 1H,H5); 4.09 (m, 1H, H8); 3.05 (m, 2H, H3″); 2.88 (m, 2H, H4″″); 2.56 (m,2H, H4′″); 2.56 (s, 3H, 7′″-CH₃); 2.53 (s, 3H, 5′″-CH₃); 2.49 (m, 2H,H1′); 2.08 (s, 3H, 8′″-CH₃); 1.74 (m, 2H, H3′″); 1.55 (m, 4H, H1″ andH1″″); 1.41 (s, 9H, C(CH₃)₃); 1.32 (m, 2H, H3″″); 1.26 (s, 6H,2×2′″-CH₃); 1.15 (m, 4H, H2″ and H2″″). Mass Spectrum (ES, +ve) m/z 1298(5%) [MH⁺], 1172 (100%). HRMS calcd for C₇₄H₈₈N₇O₁₂S 1298.6212, found1298.6185.

Benzyl(2S,5R,8R)-2-allyl-3,6,9-triaza-8-(tert-butoxycarboxamidobutyl)-5-(3-[{2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl}guanidino]propyl)-11-(2-[2′-{3-phenylpropyloxy}-[1,1′]-(S)-binaphthalen-2-yloxy])-4,7,10-trioxoundecanoate(127)

The title compound was synthesised using the general peptide couplingprocedure (Procedure B), from 112 (124 mg, 0.14 mmol) and 107 (68 mg,0.14 mmol) to afford 127 (146 mg, 0.11 mmol, 80%) as a white solid. Mp92-98° C. ¹H NMR (CDCl₃, 300 MHz): δ 7.90 (m, 4H, ArH); 7.23 (m, 18H,ArH); 6.68 (d, J=9.0 Hz, 1H, NH); 6.27 (bs, 1H, NH); 6.21 (d, J=7.2 Hz,1H, NH); 5.65 (m, 1H, H2′); 5.12 (AB_(q), J=12.3 Hz, 2H, PhCH ₂O); 5.03(m, 2H, H3′); 4.55 (m, 2H, H5 and H2); 4.40 (AB_(q), J=14.4 Hz, 2H,H111); 4.07 (m, 1H, H8); 3.85 (m, 2H, H1′″″); 3.08 (m, 2H, H3″); 2.90(m, 4H, H4″″ and H3′″″); 2.58 (m, 2H, H4′″); 2.55 (s, 3H, 7′″-CH₃); 2.53(s, 3H, 5′″-CH₃); 2.47 (m, 2H, H1′); 2.08 (s, 3H, 8′″-CH₃); 1.99 (m, 2H,H1′); 1.74 (t, J=6.6 Hz, 2H, H13′″); 1.62 (m, 2H, H2′″″); 1.40 (s, 9H,C(CH₃)₃); 1.23 (s, 6H, 2×2′″-CH₃); 1.14 (m, 2H, H3″″); 0.95 (m, 2H,H2″); 0.77 (m, 2H, H2″″). Mass Spectrum (ES, +ve) m/z 1321 (100%) [MH⁺].HRMS calcd for C₇₄H₉₀N₇O₁₂S 1300.6368, found 1300.6356.

Benzyl(2S,5R,8R)-2-allyl-3,6,9-triaza-8-(tert-butoxycarboxamidobutyl-11-(2-[2′-(3-methylbutoxy)-{1,1′}-(S)-binaphthalen-2-yloxy])-5-(3-[{2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl}guanidino]propyl)-4,7,10-trioxoundecanoate(128)

The title compound was synthesised using the general peptide couplingprocedure (Procedure B), from 112 (121 mg, 0.14 mmol) and 105 (58 mg,0.14 mmol) to afford 128 (114 mg, 0.091 mmol, 65%) as a white solid. Mp90-94° C. ¹H NMR (CDCl₃, 300 MHz): δ 7.90 (m, 4H, ArH); 7.30 (m, 13H,ArH); 6.47 (m, 1H, NH); 6.29 (bs, 2H, NH); 6.18 (d, J=6.9 Hz, 1H, NH);5.65 (m, 1H, H2′); 5.13 (AB_(q), J=12.3 Hz, 2H, PhCH ₂O); 5.05 (m, 2H,H3′); 4.80 (m, 5H, H2, H5, H8 and H11); 3.95 (m, 2H, H1′″″); 3.14 (m,2H, H3″); 2.92 (m, 2H, H4″″); 2.64 (m, 2H, H4′″); 2.56 (s, 3H, 7′″-CH₃);2.55 (s, 3H, 5′″-CH₃); 2.49 (m, 2H, H1′); 2.09 (s, 3H, 8′″-CH₃); 1.76(t, J=5.7 Hz, H3′″); 1.52 (m, 4H, H1″ and H1″″); 1.41 (s, 9H, C(CH₃)₃);1.26 (s, 6H, 2×2′″-CH₃); 1.12 (m, 2H, H3′″″); 0.92 (m, 2H, H2″″); 0.79(m, 4H, H3″″ and H2″); 0.52 (d, J=6.3 Hz, 3H, H4_(a)′″″); 0.46 (d, J=6.3Hz, 3H, H4_(b)′″″). Mass Spectrum (ES, +ve) m/z 1274 (100%) [MNH₄ ⁺].HRMS calcd for C₇₀H₉₀N₇O₁₂S 1252.6368, found 1252.6388.

Benzyl(2S,5R,8R,11S)-2-allyl-11-(4-[9-anthracenyl]benzyl)-3,6,9,12-tetraaza-8-(4-[tert-butoxycarboxamido]butyl)-5-([{2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl}guanidino]propyl)-4,7,10,13-tetraoxotetradecanoate(129)

The title compound was synthesised using the general peptide couplingprocedure (Procedure B), from 112 (40 mg, 0.045 mmol) and 97 (17 mg,0.045 mmol) to afford 129 (20 mg, 0.016 mmol, 36%) as a white solid. Mp108-110° C. ¹H NMR (CDCl₃ 300 MHz): δ 8.48 (s, 1H, ArH10′″″); 8.03 (m,2H, ArH); 7.58 (m, 2H, ArH); 7.44 (m, 2H, ArH); 7.30 (m, 11H, ArH); 6.82(bs, 1H, NH); 6.36 (bs, 2H, n 2×NH's); 5.77 (m, 1H, H2′); 5.12 (m, 4H,H3′ and PhCH ₂O); 4.85 (m, 1H, H11); 4.59 (m, 1H, H2); 4.44 (m, 1H, H5);4.31 (m, 1H, H8); 3.19 (m, 2H, 11-CH₂); 2.95 (m, 4H, H4″″ and H3″); 2.56(s, 3H, 7′″-CH₃); 2.54 (s, 3H, 5′″-CH₃); 2.52 (m, 4H, H4′″ and H1′);2.06 (s, 3H, 8′″-CH₃); 1.97 (m, 2H, H3″″); 1.94 (s, 3H, H14); 1.74 (m,4H, H1″ and H1″″); 1.71 (m, 2H, H13′″); 1.62 (m, 2H, H2″); 1.38 (m, 2H,H2″″); 1.36 (s, 9H, C(CH₃)₃); 1.23 (s, 6H, 2×2′″-CH₃). Mass Spectrum(ES, +ve) m/z 1221 (10%) [MH⁺]; 282 (100%). HRMS calcd for C₆₈H₈₅N₈O₁₁S1221.6059, found 1221.6089.

Benzyl(2S,5R,8R,11S)-2-allyl-3,6,9,12-tetraaza-8-(4-[tert-butoxycarboxamido]butyl)-5-([{2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl}guanidino]propyl)-4,7,10,13-tetraoxo-11-(4-[9-phenanthrenyl]benzyl)tetradecanoate(130)

The title compound was synthesised using the general peptide couplingprocedure (Procedure B), from 112 (38 mg, 0.044 mmol) and 99 (16 mg,0.042 mmol) to afford 130 (41 mg, 0.034 mmol, 80%) as a white solid. Mp108° C. ¹H NMR (CDCl₃, 300 MHz): δ 8.72 (m, 2H, ArH); 7.58 (m, 16H,ArH); 6.40 (bs, 2H, NH); 5.71 (m, 1H, H2′); 5.13 (m, 2H, PhCH _(—)2);5.03 (m, 2H, H3′); 4.83 (m, 1H, H11); 4.60 (m, 1H, H2); 4.59 (m, 1H,H5); 4.29 (m, H, H8); 3.12 (m, 2H, 11-CH₂); 2.94 (m, 4H, H4″″ and H3″);2.56 (s, 3H, 7′″-CH₃); 2.54 (s, 3H, 5′″-CH₃); 2.53 (m, 4H, H4′″ andH1′); 2.07 (s, 3H, 8′″-CH₃); 1.91 (s, 3H, H14); 1.82 (m, 4H, H1″ andH1″″); 1.72 (t, J=6.6 Hz, 2H, H3′″); 1.62 (m, 4H, H2″ and H3″″); 1.39(m, 2H, H2″″); 1.34 (s, 9H, C(CH₃)₃); 1.23 (s, 6H, 2×2′″-CH₃). MassSpectrum (ES, +ve) m/z 1221 (100%) [MH⁺]. HRMS calcd for C₆₈H₈₅N₈O₁₁S1221.6059, found 1221.6045.

Benzyl(2S,5R,8R)-3,6,9-triaza-8-(tert-butoxycarboxamidobutyl)-5-(3-[{2,2,5,7,8-pentamethyl-3,4-dihydro-2H-6-chromenylsulfonyl}guanidino]propyl)-4,7,10-trioxo-2-propyl-1-(2-[2′-3-(propyloxy)-{1,1′}-(S)-binaphthalen-2-yloxy])undecanoate(131)

To a solution of 122 (170 mg, 0.145 mmol) in THF (5 mL) was addedpalladium on activated carbon. The reaction vessel was degassed undervacuum and regassed with hydrogen before being allowed to stir for 13 h.The solution was filtered, evaporated to dryness and dissolved inacetone (5 mL). To this solution was added K₂CO₃ (39 mg, 0.28 mmol) andbenzyl bromide (24 mg, 0.14 mmol). After a further 13 h the reaction wasconcentrated by vacuum and the product isolated by flash columnchromatography (5% MeOH/DCM) to yield 131 (127 mg, 0.10 mmol, 71%) as awhite solid. Mp 118-123° C. ¹H NMR (CDCl₃, 300 MHz): δ 7.90 (m, 4H,ArH); 7.30 (m, 13H, ArH); 6.26 (bs, 2H, NH); 6.20 (d, J=7.2 Hz, 1H, NH);5.13 (AB_(q), J=12.6 Hz, 2H, PhCH ₂); 4.50 (m, 2H, H2 and H5) 4.43 (m,2H, H11); 3.99 (m, 1H, H8); 3.69 (m, 2H, H1′″″); 3.13 (m, 2H, H3″); 2.91(m, 2H, H4″″); 2.60 (m, 2H, H4′″); 2.56 (s, 3H, 7′″-CH₃); 2.54 (s, 3H,5′″-CH₃); 2.08 (s, 3H, 8′″-CH₃); 1.90 (m, 2H, H1′); 1.88 (m, 2H,H12′″″); 1.76 (m, 2H, H13′″); 1.58 (m, 2H, H2″″); 1.41 (s, 9H, C(CH₃)₃);1.38 (m, 4H, H1″ and H1″″); 1.34 (m, 2H, H2′); 1.27 (s, 6H, 2×2′″-CH₃);1.20 (m, 2H, H2″); 0.87 (t, J=6.9 Hz, 3H, H3′″″); 0.43 (t, J=7.2 Hz, 3H,H3′). Mass Spectrum (ES, +ve) 7m/z 1226 (100%) [MH⁺]. HRMS calcd forC₆₈H₈₈N₇O₁₂S 1226.6212, found 1226.6240.

Benzyl(2S,5R,8R)-2-allyl-11-(2-[2′-allyloxy-{1,1′}-(S)-binaphthalen-2-yloxy])-3,6,9-triaza-8-(butylamino)-5-(3-guanidinopropyl)-4,7,10-trioxoundecanoatedihydrochloride (132)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 122 (65 mg, 0.055 mmol) to yield 132 (29mg, 0.034 mmol, 62%) as a highly hydroscopic cream solid. ¹H NMR (CD₃OD,300 MHz): δ 8.04 (d, J=6.0 Hz, 1H, ArH); 8.01 (d, J=6.0 Hz, 1H, ArH);7.93 (s, 1H, ArH); 7.90 (s, 1H, ArH); 7.55 (d, J=9.3 Hz, 1H, ArH); 7.48(d, J=9.3 Hz, 1H, ArH); 7.35 (m, 7H, ArH); 7.23 (m, 2H, ArH); 7.07 (m,1H, ArH); 7.05 (m, 1H, ArH); 5.73 (m, 2H, H-2′ and H2″″); 5.16 (AB_(q),J=3.6 Hz, 2H, PhCH ₂O); 5.01 (m, 4H, H3′ and H3″″); 4.55 (m, 6H, H2, H5,H11 and H1″″); 4.13 (m, 1H, H8); 3.13 (m, 2H, H3″); 2.77 (m, 2H, H14′″);2.54 (ddd, J=5.4, 14.4, 24.3 Hz, 2H, H1′); 1.77 (m, 2H, H1″); 1.62 (m,2H, H1′″); 1.52 (m, 2H, H3′″); 1.44 (m, 2H, H2″); 0.95 (m, 2H, H2″″).¹³C NMR (CD₃OD, 75 MHz): δ 173.8, C4; 173.2, C2; 172.5, C7; 170.9, C10;158.5, CN₃; 155.4, ArC; 154.1, ArC; 137.1, ArC; 135.1, C2′; 135.1, C2″″;135.0, ArC; 134.2, ArC; 131.4, ArCH; 131.0, ArCH; 130.8, ArCH; 130.8,ArCH; 129.6, ArC; 129.4, ArC; 129.3, ArCH; 129.3, ArCH; 129.2, ArCH;127.6, ArCH; 127.6, ArCH; 126.4, ArCH; 126.0, ArCH; 125.3, ArCH; 124.9,ArCH; 21.6, ArCH; 120.5, ArC; 119.1, ArC; 117.0, C3′; 116.9, C3″″;116.0, ArCH; 70.9, C11; 69.2, C1″″; 68.1, ArCH₂; 53.9, C5; 53.7, C2;53.6, C8; 41.9, C3″; 40.4, C4′″; 36.7, C1′; 32.2, C1″; 30.3, C1′″; 27.8,C2″; 26.2, C2′″; 23.2, C3′″. Mass Spectrum (ES, +ve) 7m/z 856 (100%)[M²⁺]. HRMS calcd for C₄₉H₅₈N₇O₇ 856.4398, found 856.4367.

Benzyl(2S,5R,8R,11S)-2-allyl-11-(4-allyloxybenzyl)-8-(4-aminobutyl)-3,6,9,12-tetraaza-5-(3-[guanidino]propyl)-4,7,10,13-tetraoxotetradecanoatehydrochloride (133)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 123 (65 mg, 0.059 mmol) to yield 133 (39mg, 0.048 mmol, 82%) as a cream solid. Mp 108° C. ¹H NMR (CDCl₃, 300MHz): δ 7.35 (m, 5H, ArH); 7.16 (d, J=8.7 Hz, 2H, ArH2′″ and ArH6′″);6.87 (d, J=8.7 Hz, 2H, ArH3′″ and ArH5′″); 6.02 (m, 1H, H12′″); 5.78 (m,1H, H2′); 5.39 (dd, J=1.8, 17.1 Hz, 1H, H3_(a)′″″); 5.24 (dd, J=1.8,10.5 Hz, 1H, H3_(b)′″″); 5.10 (m, 4H, H3′ and PhCH ₂O); 4.52 (m, 2H,H1′″″); 4.39 (m, 2H, H13 and H2); 4.24 (dd, J=4.8, 9.0 Hz, 1H, H5); 3.98(dd, J=3.9, 9.9 Hz, 1H, H8); 3.16 (m, 2H, H3″); 2.94 (m, 2H, 11-CH₂);2.84 (m, 2H, H4′″); 2.55 (m, 2H, H1′); 1.94 (s, 3H, H14); 1.87 (m, 2H,H1″); 1.73 (m, 2H, H1′″); 1.54 (m, 4H, H2″ and H2′″); 1.03 (m, 2H,H3′″). ¹³C NMR (CDCl₃, 75 MHz): δ 175.4, C1; 174.4, C4; 174.2, C7;172.5, C10; 159.0, C13; 158.5, NCO; 137.2, ArC4″″; 134.9, C2′″″; 134.3,C2′; 131.5, ArC; 130.0, ArCH2″″ and ArCH6″″; 129.6, ArCH; 129.4, ArCH;129.4, ArCH; 128.5, ArC1″; 119.0, C3′; 117.6, C3′″″; 115.9, ArCH3′″ andArCH5′″; 69.8, C1′″″; 67.9, CH₂-ester); 57.8, C11; 55.3, C5; 54.8, C8;54.0, C2; 41.9, C3″; 40.3, C4′″; 37.4, 11-CH₂; 36.5, C1′; 31.2, C1′″;29.5, C2″; 28.0, C2′″; 26.5, C14; 23.8, C3′″; 22.5, C1″. Mass Spectrum(ES, +ve) m/z 735 2 [M²⁺] (70%), 368 (100%). HRMS calcd for C₃₈H₅₅N₈O₇735.4194, found 735.4200.

Benzyl(2S,5R,8R)-2-allyl-3,6,9-triaza-11-(2-[2′-benzyloxy-{1,1′}-(S)-binaphthalen-2-yloxy])-8-(butylamino)-5-(3-guanidinopropyl)-4,7,10-trioxoundecanoatedihydrochloride (134)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 124 (50 mg, 0.039 mmol) to yield 134 (29mg, 0.030 mmol, 76%) as a cream solid. Mp 116-118° C. ¹H NMR (CD₃OD, 300MHz): δ 7.70 (m, 4H, ArH); 6.91 (m, 18H, ArH); 5.54 (m, 1H, H2′); 4.89(m, 6H, PhCH ₂O, H1″″ and H3′); 4.49 (m, 1H, H2); 4.30 (m, 1H, H5); 4.23(m, 2H, H11); 4.05 (m, 1H, H8); 3.21 (m, 2H, H3″); 2.95 (m, 2H, H4′″);2.50 (m, 2H, H1′); 1.62 (m, 2H, H1″); 1.43 (m, 4H, H1′″ and H3′″); 1.15(m, 2H, H2″); 0.89 (m, 2H, H2′″). ¹³C NMR (CD₃OD, 75 MHz): δ 173.6, C4;173.4, C2; 172.4, C7; 171.1, C10; 158.2, CN₃; 154.3, ArC; 154.1, ArC;153.4, ArC; 142.1, ArC; 141.8, ArC; 140.8, ArC; 136.8, ArCH; 135.9,ArCH; 135.2, C2′; 132.6, ArC; 131.1, ArCH; 130.6, ArCH; 130.1, ArCH;129.7, ArC; 129.6, ArC; 129.5, ArCH; 129.3, ArCH; 129.2, ArCH; 129.1,ArCH; 128.8, ArCH; 127.4, ArCH; 126.9, ArCH; 126.7, ArCH; 126.3, ArCH;125.5, ArCH; 125.1, ArCH; 120.6, ArCH; 120.2, ArCH; 119.2, ArC; 116.6,C3′; 68.7, C11; 68.7, C1″″; 68.0, ArCH₂; 54.0, C5; 53.9, C2; 53.6, C8;41.8, C3″; 40.4, C4′″; 36.5, C1′; 31.9, C1″; 30.0, C1′″; 27.6, C2″;26.1, C2′″; 23.2, C3′″. Mass Spectrum (ES, +ve) m/z 906 (100%) [M²⁺].HRMS calcd for C₅₃H₆₀N₇O₇ 906.4554, found 906.4544.

Benzyl(2S,5R,8R)-2-allyl-3,6,9-triaza-8-(butylamino)-5-(3-guanidinopropyl)-11-(2-[2′-methyloxy-{1,1′}-(S)-binaphthalen-2-yloxy])-4,7,10-trioxoundecanoatedihydrochloride (135)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 125 (45 mg, 0.037 mmol) to yield 135 (24mg, 0.027 mmol, 72%) as a highly hydroscopic cream solid. ¹H NMR (CD₃OD,300 MHz): δ 7.76 (m, 4H, ArH); 7.03 (m, 13H, ArH); 5.56 (m, 1H, H2′);4.94 (m, 4H, PhCH ₂O and H3′); 4.31 (m, 4H, H2, H5 and H11); 4.03 (m,1H, H8); 3.56 (s, 3H, OCH₃); 2.98 (m, 2H, H3″); 2.64 (m, 2H, H4′″); 2.36(m, 2H, H1′); 1.42 (m, 4H, H1″ and H1′″); 0.99 (m, 2H, H2″); 0.78 (m,2H, H2″″). ¹³C NMR (CD₃OD, 75 MHz): δ 173.7, C4; 173.1, C2; 172.4, C7;170.8, C10; 158.4, CN₃; 156.2, ArC; 153.8, ArC; 136.9, ArC; 135.0, ArC;134.8, C2′; 134.1, ArCH; 131.2, ArC; 131.0, ArCH; 130.9, ArCH; 130.5,ArC; 129.5, ArCH; 129.3, ArCH; 129.2, ArCH; 129.2, ArC; 129.1, ArCH;127.6, ArC; 127.5, ArCH; 126.1, ArCH; 125.7, ArCH; 125.2, ArCH; 124.7,ArCH; 121.4, ArC; 119.5, ArCH; 119.2, C3′; 116.0, ArCH; 115.3, ArCH;69.1, C11; 68.0, ArCH₂; 57.2, OCH₃; 54.0, C5; 53.6, C2; 53.6, C8; 41.9,C3″; 40.5, C4′″; 36.6, C1′; 32.2, C1″; 30.1, C1′″; 27.7, C2″; 26.2,C2′″; 23.1, C3′″. Mass Spectrum (ES, +ve) m/z 830 (100%) [M²⁺]. HRMScalcd for C₄₇H₅₆N₇O₇ 830.4241, found 830.4219.

Benzyl(2S,5R,8R)-2-allyl-3,6,9-triaza-8-(butylamino)-5-(3-guanidinopropyl)-11-(2-[2′-hydroxy-{1,1′}-(S)-binaphthalen-2-yloxy])-4,7,10-trioxoundecanoatedihydrochloride (136)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 126 (50 mg, 0.038 mmol) to yield 136 (35mg, 0.036 mmol, 96%) as a highly hydroscopic cream solid. ¹H NMR (CD₃OD,300 MHz): δ 7.62 (m, 4H, ArH); 6.90 (m, 13H, ArH); 5.44 (m, 1H, H2′);4.82 (m, 4H, PhCH ₂° and H3′); 4.40 (m, 1H, H5); 4.31 (m, 2H, H11); 4.21(m, 1H, H2); 3.96 (m, 1H, H8); 2.86 (m, 2H, H3″); 2.54 (m, 2H, H4′″);2.26 (m, 2H, H1′); 1.54 (m, 2H, H1″); 1.34 (m, 4H, H3′″ and H1′″); 1.05(m, 2H, H2″); 0.79 (m, 2H, H2″″). ¹³C NMR (CD₃OD, 75 MHz): δ 173.6, C4;173.4, C2; 172.4, C7; 171.1, C10; 158.2, CN₃; 154.0, ArC; 153.3, ArC;136.7, ArC; 135.2, ArC; 135.0, C2′; 133.9, ArCH; 131.0, ArCH; 130.8,ArC; 130.6, ArCH; 130.0, ArCH; 129.4, ArCH; 129.2, ArCH; 129.1, ArCH;128.1, ArC; 127.8, ArCH; 127.5, ArC; 127.3, ArC; 126.2, ArCH; 125.5,ArCH; 125.1, ArCH; 124.1, ArCH; 120.5, ArC; 119.5, ArCH; 119.2, C3′;116.5, ArCH; 115.5, ArCH; 68.6, C11; 67.9, ArCH₂; 54.0, C5; 53.9, C2;53.5, C8; 41.7, C3″; 40.3, C4′″; 36.4, C1′; 32.0, C1″; 30.0, C1′″; 27.6,C2″; 26.0, C2′″; 23.2, C3′″. Mass Spectrum (ES, +ve) m/z 888 (5%) [M²⁺],831 (100%). HRMS calcd for C₄₆H₅₄N₇O₇ 816.4085, found 816.4086.

Benzyl(2S,5R,8R)-2-allyl-3,6,9-triaza-8-(butylamino)-5-(3-guanidinopropyl)-4,7,10-trioxo-11-(2-[2′-(3-phenylpropyloxy)-{1,1′}-(S)-binaphthalen-2-yloxy])-undecanoatedihydrochloride (137)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 127 (146 mg, 0.11 mmol) to yield 137 (91mg, 0.090 mmol, 82%) as a highly hydroscopic cream solid. ¹H NMR (CD₃OD,500 MHz): δ 7.95 (m, 4H, ArH); 7.15 (m, 18H, ArH); 5.73 (m, 1H, H2′);5.10 (m, 4H, H3′ and PhCH ₂O); 4.47 (m, 1H, H5); 4.35 (m, 2H, H11); 4.17(m, 1H, H2); 4.08 (m, 1H, H8); 3.86 (m, 2H, H1″″); 3.13 (m, 2H, H3″);2.80 (m, 2H, H2″″); 2.52 (m, 2H, H4′″); 2.10 (m, 2H, H1′); 1.61 (m, 4H,H3″″ and H1″); 1.49 (m, 4H, H3′ and H1′″); 1.12 (m, 2H, H2″); 0.96 (m,2H, H2″″). ¹³C NMR (CD₃OD, 125 MHz): δ 173.8, C4; 173.1, C2; 172.4, C7;170.7, C10; 158.5, CN₃; 155.6, ArC; 154.0, ArC; 142.7, ArC; 137.0, C2′;135.2, ArCH; 135.0, ArCH; 134.4, ArC; 134.1, ArCH; 131.3, ArC; 130.9,ArC; 130.6, ArCH; 129.6, ArCH; 129.3, ArCH; 129.3, ArCH; 129.2, ArCH;129.2, ArCH; 129.0, ArCH; 127.9, ArC; 127.6, ArCH; 126.5, ArCH; 126.4,ArC; 125.9, ArC; 125.3, ArCH; 124.8, ArCH; 121.7, ArCH; 120.9, ArCH;120.3, ArC; 119.1, C3′; 116.7, ArCH; 116.0, ArCH; 69.3, C11; 69.2,ArCH₂; 68.0, C1″″; 54.1, C5; 53.6, C2; 53.5, C8; 41.9, C3″; 40.3, C4′″;36.6, C1′; 32.5, C1″; 32.2, C1′″; 32.1, C3″″; 30.1, C2″″; 27.7, C2″;26.2, C2′″; 23.1, C3′″. Mass Spectrum (ES, +ve) m/z 934 (5%) [M²⁺], 468(100%). HRMS calcd for C₅₅H₆₄N₇O₇ 934.4867, found 934.4844.

Benzyl(2S,5R,8R)-2-allyl-3,6,9-triaza-8-(butylamino)-5-(3-guanidinopropyl)-11-(2-[2′-(3-methylbutoxy)-{1,1′}-(S)-binaphthalen-2-yloxy])-4,7,10-trioxoundecanoatedihydrochloride (138)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 128 (114 mg, 0.091 mmol) to yield 138 (48mg, 0.050 mmol, 55%) as a highly hydroscopic cream solid. ¹H NMR (CD₃OD,500 MHz): δ 7.968 (m, 4H, ArH); 5.32 (m, 13H, ArH); 5.74 (m, 1H, 1H2′);5.11 (m, 4H, PhCH ₂O and H3′); 4.49 (m, 3H, H5 and H11); 4.35 (m, 1H,H2); 4.14 (m, 2H, H1″″); 3.95 (m, 1H, H8); 3.14 (m, 2H, H3″); 2.79 (m,2H, H4″); 2.55 (m, 2H, H1′); 1.79 (m, 2H, H1″); 1.71 (m, 2H, H3′″); 1.55(m, 4H, H2″″ and H1′″); 1.24 (m, 2H, H3″″); 1.17 (m, 2H, H2″); 0.96 (m,2H, H12′″); 0.53 (d, J=6.3 Hz, 3H, H4_(a)″″); 0.47 (d, J=6.3 Hz, 3H,H4_(b)″″)-¹³C NMR (CD₃OD, 125 MHz): δ 173.9, C4; 173.2, C2; 172.5, C7;170.9, C10; 158.5, CN₃; 155.9, ArC; 154.0, ArC; 137.1, C2′; 135.2, ArC;135.0, ArC; 134.3, ArCH; 134.2, ArCH; 131.4, ArC; 129.6, ArCH; 129.6,ArCH; 129.4, ArCH; 129.3, ArC; 129.1, ArCH; 128.2, ArC; 128.0, ArC;127.6, ArCH; 127.5, ArCH; 126.4, ArCH; 126.0, ArCH; 125.2, ArC; 124.8,ArCH; 121.8, ArCH; 120.5, ArCH; 119.1, C3′; 117.0, ArCH; 116.0, ArCH;69.0, ArCH₂; 68.0, C11; 65.2, C1″″; 54.2, C5; 53.7, C2; 53.6, C8; 41.9,C3″; 40.4, C4′″; 39.3, C2″″; 36.7, C1′; 32.2, C1″; 30.1, C2″; 27.7,C2′″; 26.2, C3″″; 25.6, C3″″; 22.8, C4_(a″″; 22.6), C4_(b)″″. MassSpectrum (ES, +ve) m/z 886 (5%) [M²⁺], 444 (100%). HRMS calcd forC₅₁H₆₄N₇O₇ 886.4867, found 886.4869.

Benzyl(2S,5R,8R,11S)-2-allyl-8-(4-aminobutyl)-11-(4-[9-anthracenyl]benzyl)-3,6,9,12-tetraaza-5-(3-guanidinopropyl)-4,7,10,13-tetraoxotetradecanoate(139)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 129 (20 mg, 0.016 mmol) to yield 139 (13mg, 0.014 mmol, 88%) as a white solid. Mp 218-220° C. ¹H NMR (CD₃OD, 300MHz): δ 7.68 (m, 17H, ArH); 5.77 (m, 1H, H2′); 5.15 (m, 4H, H3′ and PhCH₂O); 4.82 (m, 1H, H11); 4.42 (m, 1H, H2); 4.25 (m, 1H, H5); 4.07 (m, 1H,H8); 3.18 (m, 2H, 11-CH₂); 2.88 (m, 4H, H4″″ and H3″); 2.55 (m, 2H,H1′); 1.95 (s, 3H, H14); 1.85 (m, 2H, H1″); 1.65 (m, 2H, H1′″); 1.53 (m,2H, H2″); 0.94 (m, 2H, H2′″). ¹³C NMR (CD₃OD, 75 MHz): δ 175.2, C13;174.4, C1; 174.2, C4; 174.1, C10; 172.5, C7; 158.6, CN₃; 140.0, ArC;139.9, ArC; 138.1, ArC; 137.4, ArC; 133.2, ArC; 134.3, C2′; 131.5, ArC;131.3, ArCH; 130.1, ArCH; 129.2, ArC; 128.1, ArC; 127.9, ArCH; 127.6,ArCH; 127.5, ArCH; 126.6, ArCH; 125.9, ArCH; 125.8, ArCH; 125.6, ArCH;124.2, ArCH; 119.1, C3′; 68.1, CH₂-ester; 57.9, C11; 55.3, C8; 54.7, C5;54.2, C2; 42.1, C3″; 40.3, C4′″; 38.1, 11-CH₂; 36.7, C1′; 31.4, C1″:29.4, C1′″; 27.3, C14; 26.5, C2″; 23.6, C3′″; 22.5, C2′″. (Mass Spectrum(ES, +ve) m/z 855 (50%) [M²⁺]; 428 (100%). HRMS calcd for C₄₉H₅₉N₈O₆855.4558, found 855.4539.

Benzyl(2S,5R,8R,11S)-2-allyl-8-(4-aminobutyl)-3,6,9,12-tetraaza-5-(3-guanidinopropyl)-4,7,10,13-tetraoxo-11-(4-[9-phenanthrenyl]benzyl)tetradecanoate(140)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 130 (42 mg, 0.034 mmol) to yield 140 (25mg, 0.027 mmol, 79%) as a white solid. Mp 215-220° C. ¹H NMR (CD₃OD, 300MHz): δ 8.82 (m, 2H, ArH); 7.60 (m, 16H, ArH); 5.81 (m, 1H, H2′); 5.15(m, 4H, PhCH ₂O and H3′); 4.58 (m, 1H, H11); 4.43 (m, 1H, H2); 4.35 (dd,J=4.8, 9.0 Hz, 1H, H5); 4.17 (dd, J=4.8, 9.6 Hz, 1H, H8); 3.17 (m, 4H,H4″″ and H3″); 2.72 (m, 2H, 11-ArCH₂); 2.59 (m, 1H, H1′); 1.96 (s, 3H,H14); 1.80 (m, 4H, H1″ and H1′″); 1.65 (m, 2H, H3′″); 1.51 (m, 2H, H2″);1.22 (m, 2H, H2′″). ¹³C NMR (CD₃OD, 75 MHz): δ 175.2, C13; 174.4, C1;174.2, C4; 174.1, C10; 172.5, C7; 158.6, CN₃; 140.7, ArC; 139.6, ArC;137.4, ArC; 137.2, ArC; 134.3, C2′; 132.9, ArC; 132.1, ArC; 131.3, ArCH;130.5, ArCH; 129.7, ArC; 129.6, ArC; 129.4, ArCH; 129.4, ArCH; 128.5,ArCH; 128.1, ArCH; 127.9, ArCH; 127.8, ArCH; 127.6, ArCH; 124.2, ArCH;123.7, ArCH; 12.4, ArCH; 122.1, ArCH; 121.8, ArCH; 119.0, C3′; 68.0,CH₂-ester; 57.7, C11; 55.2, C8; 54.7, C5; 54.0, C2; 42.0, C3″; 40.1,C4′″; 38.1, 11-CH₂; 36.6, C1′; 31.3, C1″: 29.6, C1′″; 27.8, C14; 26.4,C2″; 23.8, C3′″; 22.6, C2′″. Mass Spectrum (ES, +ve) m/z 855 (30%)[M²⁺], 428 (100%). HRMS calcd for C₄₉H₅₉N₉O₆ 855.4558, found 855.4528.

Benzyl(2S,5R,8R)-3,6,9-triaza-8-(4-aminobutyl)-5-(3-guanidinopropyl)-4,7,10-trioxo-2-propyl-11-(2-[2′-3-(propyloxy)-{1,1′}-(S)-binaphthalen-2-yloxy])undecanoate(141)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 131 (115 mg, 0.094 mmol) to yield 141 (75mg, 0.080 mmol, 85%) as a highly hydroscopic white solid. ¹H NMR (CD₃OD,500 MHz) δ 7.95 (m, 4H, ArH); 7.30 (m, 13H, ArH); 5.11 (m, 2H, PhCH ₂O);4.58 (m, 2H, H111); 4.39 (m, 1H, H5); 4.15 (m, 1H, H2); 4.89 (m, 1H,H8); 3.68 (m, 2H, H1″″); 3.17 (m, 2H, H3″); 2.55 (m, 2H, H4′″); 2.07 (m,4H, H11′ and H2″″); 1.38 (m, 6H, H1″, H3′″ and H11′″); 1.34 (m, 2H,H2′); 1.13 (m, 2H, H12′″); 1.08 (m, 2H, H2″); 0.89 (m, 3H, H3″″); 0.50(m, 3H, H3′). ¹³C NMR (CD₃OD, 125 MHz) δ 173.9, C4; 173.3, C2; 173.1,C7; 170.8, C10; 158.4, CN₃; 155.8, ArC; 153.9, ArC; 142.6, ArC; 137.1,ArC; 135.1, ArCH; 135.1, ArCH; 131.3, ArC; 130.9, ArC; 130.6, ArC;129.6, ArCH; 129.3, ArCH; 129.3, ArCH; 129.1, ArC; 128.2, ArC; 127.6,ArCH; 127.4, ArCH; 126.3, ArCH; 125.9, ArCH; 125.2, ArCH; 124.8, ArCH;11.7, ArCH; 120.4, ArCH; 116.8, ArCH; 116.0, ArCH; 72.1, C1″″; 69.2,C11; 67.9, ArCH₂; 54.1, C5; 53.7, C2; 53.6, C8; 41.9, C3″; 40.4, C4′″;34.3, C1′; 32.2, C1″; 30.1, C1′″; 27.7, C2″; 26.2, C2″″; 23.7, C2′″;23.1, C3′″; 20.0, C2′; 13.9, C3′; 10.8, C3″″. Mass Spectrum (ES, +ve)m/z 860 (30%) [M²⁺], 431 (100%). HRMS calcd for C₄₉H₆₂N₇O₇ 860.4711,found 860.4730.

Methyl 3-amino-benzoate hydrochloride (143)

To a suspension of 3-aminobenzoic acid (1.03 g mg, 7.52 mmol) in MeOH(80 mL) at 0° C. was added dropwise thionyl chloride (5 mL). Theresulting solution was allowed to stir for 16 h before the solvent wasremoved by evaporation and the product precipitated with diethyl ether.The diethyl ether was removed by evaporation to yield the title compound(1.38 g, 7.38 mmol, 98%) as a white solid. Mp 176-178° C. ¹H NMR (D₂O,300 MHz): δ 7.75 (dt, J=1.8, 3.3, 7.2 Hz, 1H, ArH); 7.71 (m, 1H, ArH);7.42 (m, 1H, ArH); 7.37 (m, 1H, ArH); 3.66 (s, 3H, OCH₃). Mass Spectrum(CI) m/z 152 (100%) [M⁺]. HRMS calcd for C₈H₁₀NO₂ 152.0712, found152.0698.

Methyl(3′R)-3-(1-aza-6-tert-butoxycarboxamido-3′-[9H-9-fluororenylmethoxycarboxamido]-2-oxohexyl)benzoate(144)

The title compound was synthesised using the general peptide couplingprocedure (Procedure B), from 143 (220 mg, 2.27 mmol) and(R)-5-(tert-butoxycarboxamido)-2-(9H-9-fluorenylmethyloxycarboxamido)pentanoicacid (578 mg, 1.27 mmol) to afford 144 (277 mg, mmol, 36%) as a whitesolid. Mp 96-98° C. ¹H NMR (CDCl₃, 300 MHz): δ 9.15 (s, 1H, ArH); 8.17(s, 1H, NH); 7.88 (d, J=8.1 Hz, 1H, ArH); 7.77 (m, 1H, ArH1); 7.72 (d,J=7.8 Hz, 2H, ArH1″ and ArH8″); 7.56 (d, J=7.2, Hz, 2H, ArH4″ andArH5″); 7.36 (m, 2H, ArH3″ and ArH6″); 7.26 (m, 2H, ArH2″ and ArH7″);6.03 (d, J=8.1 Hz, 2H, NH); 4.63 (m, 1H, H3′); 4.36 (d, J=6.9 Hz, 2H,OCH ₂—H9″); 4.17 (t, J=6.9 Hz, 1H, H9″); 3.86 (s, 3H, OCH₃); 3.08 (m,2H, H6′); 1.78 (m, 2H, H4′); 1.60 (m, 2H, H5′); 1.42 (s, 9H, (CH₃)₃).Mass Spectrum (ES, +ve) m/z 610 (100%) [MNa⁺], 588 (70%) [MH⁺]. HRMScalcd for C₃₃H₃₈N₃O₇ 588.2710, found 588.2726.

Methyl(3R)-3-(3′-amino-1-aza-6-tert-butoxycarboxamido-2-oxohexyl)benzoate(145)

The title compound was synthesized using the general N-Fmoc deprotectionprocedure (Procedure C), from 144 (555 mg, 0.95 mmol) to yield 145 (285mg, 0.78 mmole, 82%) as a colourless viscous oil. ¹H NMR (CDCl₃, 300MHz): δ 8.04 (m, 1H, ArH); 7.84 (t, J=1.8 Hz, 1H, ArH); 7.51 (t, J=7.8Hz, 1H, ArH); 7.36 (m, 1H, ArH); 5.11 (m, 1H, NH); 3.91 (s, 3H, OCH₃);3.69 (m, 1H, H3′); 3.19 (m, 2H, H6′); 2.08 (m, 2H, H4′); 1.65 (m, 4H,H5′ and NH₂); 1.43 (s, 9H, (CH₃)₃). HRMS calcd for C₁₈H₂₈N₃O₅ 366.2029,found 366.2051.

Methyl(3R)-3-(6-(2-[2′-allyloxy-{1,1′}-(S)-binaphthalen-2-yloxy])-1,4-diaza-3-[(3-tert-butoxycarboxamido)propyl]-2,5-dioxohexyl)benzoate(146)

The title compound was synthesised using the general peptide couplingprocedure (Procedure B), from 101 (288 mg, 0.75 mmol) and 145 (275 mg,0.75 mmol) to afford 146 (434 mg, 0.59 mmol, 79%) as a white foam. Mp70° C. ¹H NMR (CDCl₃, 300 MHz): δ 9.08 (s, 1H, ArH); 7.91 (m, 7H, ArH);7.85 (m, 8H, ArH); 6.45 (d, J=8.1 Hz, 1H, NH); 5.69 (m, 1H, H2′″); 4.94(m, 2H, H3′″); 4.55 (m, 5H, H6′, H1′″ and H3′); 3.87 (s, 3H, OCH₃); 2.96(m, 2H, H3″); 1.62 (m, 2H, H1″); 1.44 (s, 9H, (CH₃)₃); 1.04 (m, 2H,H2″)″. Mass Spectrum (ES, +ve) m/z 732 (50%) [MH⁺], 351 (100%). HRMScalcd for C₄₃H₄₆N₃O₈ 732.3285, found 732.3316.

(3R)-3-(6-(2-[2′-allyloxy-{1,1′}-(S)-binaphthalen-2-yloxy])-1,4-diaza-3-[(3-tert-butoxycarboxamido)propyl]-2,5-dioxohexyl)benzoicacid (147)

To a solution of 146 (370 mg, 0.51 mmol) in THF/water, 3:1 (8 mL) wasadded lithium hydroxide monohydrate (43 mg, 0.51 mmol) and the resultingsuspension was allowed to stir for 16 h. The reaction mixture wasdiluted with water (30 mL) and the THF was removed by evaporation beforethe remaining aqueous layer was washed with diethyl ether (40 mL) toremove unreacted starting material. The aqueous phase was acidified withdilute potassium bisulfate and the resulting precipitate was extractedwith DCM (3×40 mL). The combined DCM fractions were dried and evaporatedto yield the title compound (350 mg, 0.49 mmol, 96%) as a white solid.Mp 86-90° C. ¹H NMR (CDCl₃, 300 MHz): δ 9.70 (bs, 1H, COOH); 9.26 (s,1H, ArH); 7.97 (m, 7H, ArH); 7.34 (m, 8H, ArH); 6.63 (d, J=9.0 Hz, 1H,NH); 5.71 (m, 1H, H2′″); 5.01 (m, 2H, H3′″); 4.59 (m, 5H, H6′, H1′″ andH3′); 3.03 (m, 2H, H3″); 1.65 (m, 2H, H1″); 1.49 (s, 9H, (CH₃)₃); 1.15(m, 2H, H2″). Mass Spectrum (ES, +ve) m/z 740 (100%) [MNa⁺], 718 (20%)[MH⁺]. HRMS calcd for C₄₂H₄₄N₃O₅ 718.3128, found 718.3152.

Benzyl(3R)-3-(6-(2-[2′-allyloxy-{1,1′}-(S)-binaphthalen-2-yloxy])-1,4-diaza-3-[(3-tert-butoxycarboxamido)propyl]-2,5-dioxohexyl)benzoate(148)

To a solution of 147 (40 mg, 0.056 mmol) in acetone (2 mL) was addedK₂CO₃ (17 mg, 0.12 mmol) and benzyl bromide (21 mg, 0.12 mmol). Theresulting suspension was allowed to stir for 16 h before concentrationand purification by flash column chromatography (5% MeOH/DCM) to yieldthe title compound (36 mg, 0.045 mmol, 80%) as a white solid. Mp145-152° C. ¹H NMR (CDCl₃, 300 MHz): δ 8.63 (s, 1H, ArH); 7.90 (m, 7H,ArH); 7.30 (m, 11H, ArH); 6.27 (d, J=8.4 Hz, 1H, NH); 5.68 (m, 1H,H2′″); 5.30 (s, 2H, ArCH₂); 4.87 (m, 2H, H3′″); 4.50 (m, 5H, H6′, H1′″and H3′); 3.00 (m, 2H, H3″); 1.52 (m, 2H, H1″); 1.42 (s, 9H, (CH₃)₃);1.05 (m, 2H, H2″). Mass Spectrum (ES, +ve) m/z 808 (30%) [MH⁺]; 414(100%). HRMS calcd for C₄₉H₅₀N₃O₈ 808.3598, found 808.3634.

Allyl(3R)-3-(6-(2-[2′-allyloxy-{1,1′}-(S)-binaphthalen-2-yloxy])-1,4-diaza-3-[(3-tert-butoxycarboxamido)propyl]-2,5-dioxohexyl)benzoate(149)

To a solution of 147 (43 mg, 0.060 mmol) in acetone (2 mL) was addedK₂CO₃ (18 mg, 0.12 mmol) and allyl bromide (0.1 mL, 0.12 mmol). Theresulting suspension was allowed to stir for 16 h before concentrationand purification by flash column chromatography (5% MeOH/DCM) to yieldthe title compound (36 mg, 0.047 mmol, 79%) as a white solid. Mp142-150° C. ¹H NMR (CDCl₃, 300 MHz): δ 8.75 (s, 1H, ArH); 7.90 (m, 7H,ArH); 7.29 (m, 8H, ArH); 6.32 (d, J=8.4 Hz, 1H, NH); 6.02 (m, 1H,CH-ester); 5.65 (m, 1H, H12′″); 5.39 (dd, J=1.5, 17.4 Hz, 1H,H3_(a)-ester); 5.27 (dd, J=1.5, 10.5 Hz, 1H, H3_(b)-ester); 4.89 (m, 2H,H3′″); 4.81 (m, 2H, H1-ester); 4.55 (AB_(q), J=14.7 Hz, 2H, H6′); 4.52(m, 2H, H1′″); 4.23 (m, 1H, H3′); 3.00 (m, 2H, H3″); 1.91 (m, 2H, H1″);1.44 (s, 9H, (CH₃)₃); 1.01 (m, 2H, H2″). Mass Spectrum (ES, +ve) m/z 758(10%) [MH⁺]; 444 (100%). HRMS calcd for C₄₅H₄₇N₃O₈Na 780.3261, found780.3290.

(3R)-3-(6-(2-[2′-allyloxy-{1,1′}-(S)-binaphthalen-2-yloxy])-1,4-diaza-3-[(3-tert-butoxycarboxamido)propyl]-2,5-dioxohexyl)-N-benzyloxybenzamide(150)

The title compound was synthesised using the general peptide couplingprocedure (Procedure B), from 147 (91 mg, 0.127 mmol) andO-benzylhydroxylamine (20 mg, 1.27 mmol) to afford 150 (82 mg, 0.100mmol, 78%) as a white solid. Mp 141-144° C. ¹H NMR (CDCl₃, 300 MHz): δ9.14 (s, 1H, ArH); 7.97 (m, 2H, ArH); 7.88 (m, 2H, ArH); 7.31 (m, 10H,ArH); 6.41 (d, J=7.5 Hz, 1H, NH); 5.66 (m, 1H, H12′″); 4.95 (m, 4H, H3′″and ArCH₂); 4.66 (t, J=5.1 Hz, 1H, NH); 4.54 (m, 4H, H6′, H1′″); 4.30(m, 1H, H3′); 2.93 (m, 2H, H3″); 1.54 (m, 2H, H1″); 1.43 (s, 9H,(CH₃)₃); 1.06 (m, 2H, H2″). Mass Spectrum (ES, +ve) m/z 823 (100%)[MH⁺]. HRMS calcd for C₄₉H₅₁N₄O₈ 823.3707, found 823.3726.

Methyl(3R)-3-(6-(2-[2′-allyloxy-{1,1′}-(S)-binaphthalen-2-yloxy])-1,4-diaza-3-(3[{di-tert-butoxycarbonyl}guanidino]propyl)-2,5-dioxohexyl)benzoate(151)

To a solution of 155 (32 mg, 0.048 mmol) in DCM (3 mL) was addedN1-tert-butoxycarboxamido(trifluoromethylsulfonylimino)methylpropanamide (28 mg, 0.072 mmol), triethylamine (7.3 mg, 0.072 mmol). Theresulting solution was allowed to stir for 16 h under a nitrogenatmosphere. The solvent was evaporated and the crude product waspurified by flash column chromatography (15:1, DCM/MeOH) to yield thetitle compound (41 mg, 0.047 mmole, 98%) as a white solid. Mp 74-76° C.¹H NMR (CDCl₃, 300 MHz): δ 8.55 (s, 1H, ArH); 8.27 (bs, 1H, NH); 7.77(m, 7H, ArH); 7.26 (m, 8H, ArH); 6.34 (d, J=8.4 Hz, 1H, NH); 5.59 (m,1H, H2′″); 4.67 (m, 2H, H3′″); 4.57 (d, J=3.3 Hz, 2H, H1′″); 4.48 (m,2H, C6′); 4.34 (m, 1H, H3′); 3.91 (s, 3H, OCH₃); 3.26 (m, 2H, H3″); 1.65(m, 2H, H1″); 1.51 (s, 9H, (CH₃)₃); 1.46 (s, 9H, (CH₃)₃); 1.14 (m, 2H,H2″). Mass Spectrum (ES, +ve) m/z 896 (100%) [MNa⁺], 875 (95%) [MH⁺].HRMS calcd for C₄₉H₅₆N₅O₁₀ 874.4027, found 874.4043.

Benzyl(3R)-3-(6-(2-[2′-allyloxy-{1,1′}-(S)-binaphthalen-2-yloxy])-1,4-diaza-3-(3[{di-tert-butoxycarbonyl}guanidino]propyl)-2,5-dioxohexyl)benzoate(152)

To a solution of 157 (20 mg, 0.027 mmol) in DCM (2 mL) was addedN1-tert-butoxycarboxamido(trifluoromethylsulfonylimino)methylpropanamide (16 mg, 0.041 mmol), and triethylamine (4 mg, 0.041 mmol).The resulting solution was allowed to stir for 16 h under N₂. Thesolvent was evaporated and the crude product was purified by flashcolumn chromatography (15:1, DCM/MeOH) to yield the title compound (15mg, 0.016 mmole, 58%) as a white solid. Mp 122-126° C. ¹H NMR (CDCl₃,300 MHz): δ 8.41 (s, 1H, ArH); 8.26 (bs, 1H, NH); 7.85 (m, 7H, ArH);7.32 (m, 8H, ArH); 6.31 (d, J=8.1 Hz, 1H, NH); 5.56 (m, 1H, H2′″); 5.37(s, 2H, ArCH₂); 4.85 (m, 2H, H3′″); 4.56 (m, 2H, H1′″); 4.45 (m, 2H,H6′); 4.32 (m, 1H, H3′); 3.25 (m, 2H, H3″); 1.63 (m, 2H, H1″); 1.50 (s,9H, (CH₃)₃); 1.46 (s, 9H, (CH₃)₃); 1.15 (m, 2H, H2″). Mass Spectrum (ES,+ve) m/z 950 (100%) [MH⁺]. HRMS calcd for C₅₅H₆₀N₅O₁₀ 950.4340, found950.4339.

Allyl(3R)-3-(6-(2-[2′-allyloxy-{1,1′}-(S)-binaphthalen-2-yloxy])-1,4-diaza-3-(3[{di-tert-butoxycarbonyl}guanidino]propyl)-2,5-dioxohexyl)benzoate(153)

To a solution of 159 (25 mg, 0.036 mmol) in DCM (2 mL) was addedN1-tert-butoxycarboxamido(trifluoromethylsulfonylimino)methylpropanamide (21 mg, 0.054 mmol), and triethylamine (0.1 mL). Theresulting solution was allowed to stir for 16 h under N₂. The solventwas evaporated and the crude product was purified by flash columnchromatography (15:1, DCM/MeOH) to yield the title compound (31 mg,0.034 mmole, 97%) as a white solid. Mp 70° C. ¹H NMR (CDCl₃, 300 MHz): δ8.57 (s, 1H, ArH); 8.26 (bs, 1H, NH); 7.88 (m, 7H, ArH); 7.28 (m, 8H,ArH); 6.34 (d, J=8.1 Hz, 1H, NH); 6.03 (m, 1H, CH-ester); 5.58 (m, 1H,H2′″); 5.40 (dd, J=1.5, 17.1 Hz, 1H, H3_(a)-ester); 5.28 (dd, J=1.5,10.5 Hz, 1H, H3_(b)-ester); 4.85 (m, 4H, H1-ester and H3′″); 4.50 (m,4H, H6′ and H1′″); 4.34 (m, 1H, H3′); 3.26 (m, 2H, H3″); 1.62 (m, 2H,H1″); 1.50 (s, 9H, (CH₃)₃); 1.46 (s, 9H, (CH₃)₃); 1.10 (m, 2H, H12″).Mass Spectrum (ES, +ve) m/z 900 (10%) [MH⁺], 700 (100%). HRMS calcd forC₅₁H₅₈N₅O₁₀ 900.4184, found 900.4179.

(3R)-3-(6-(2-[2′-allyloxy-{1,1′}-(S)-binaphthalen-2-yloxy])-1,4-diaza-3-(3[{di-tert-butoxycarbonyl}guanidino]propyl)-2,5-dioxohexyl)-N-benzyloxybenzamide(154)

To a solution of 161 (51 mg, 0.067 mmol) in DCM (3 mL) was addedN1-tert-butoxycarboxamido(trifluoromethylsulfonylimino)methylpropanamide (39 mg, 0.10 mmol), and triethylamine (0.1 mL). Theresulting solution was allowed to stir for 16 hr under N₂. The solventwas evaporated and the crude product was purified by flash columnchromatography (15:1, DCM/MeOH) to yield the title compound (58 mg,0.060 mmole, 90%) as a white solid. Mp 112° C. ¹H NMR (CDCl₃, 300 MHz):δ 9.05 (s, 1H, ArH); 8.25 (bs, 1H, NH); 7.90 (m, 4H, ArH); 7.31 (m, 16H,ArH); 6.34 (d, J=7.5 Hz, 1H, NH); 5.63 (m, 1H, H2′″); 5.00 (s, 2H,ArCH₂); 4.89 (m, 2H, H3′″); 4.51 (m, 4H, H6′ and H1′″); 4.25 (m, 1H,H3′); 3.23 (m, 2H, H3″); 1.65 (m, 2H, H1″); 1.50 (s, 9H, (CH₃)₃); 1.44(s, 9H, (CH₃)₃); 1.10 (m, 2H, H2″). Mass Spectrum (ES, +ve) m/z 987(100%) [MNa⁺], 965 (90%) [MH⁺]. HRMS calcd for C₅₅H₆₁N₆O₁₀ 965.4449,found 965.4422.

Methyl(3R)-3-(6-(2-[2′-allyloxy-{1,1′}-(S)-binaphthalen-2-yloxy])-3-(3-aminopropyl)-1,4-diaza-2,5-dioxohexyl)benzoatehydrochloride (155)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 146 (56 mg, 0.077 mmol) to yield 155 (38mg, 0.057 mmol, 74%) as a highly hydroscopic cream solid. ¹H NMR (CD₃OD,300 MHz): δ 8.02 (m, 2H, ArH); 7.92 (m, 2H, ArH); 7.75 (m, 2H, ArH);7.34 (m, 8H, ArH); 7.06 (m, 2H, ArH); 5.71 (m, 1H, H2′″); 4.90 (m, 2H,H3′″); 4.59 (m, 5H, H6′, H1′″ and H3′); 3.93 (s, 3H, OCH₃); 2.76 (m, 2H,H3″); 1.67 (m, 2H, H1″); 1.30 (m, 2H, H2″). ¹³C NMR (CD₃OD, 75 MHz): δ170.9, 1-CO; 170.6, C5′; 168.1, C2′; 155.4, ArC; 154.1, ArC; 139.8,C2′″; 138.0, ArC; 135.1, ArC; 134.9, ArC; 132.1, ArCH; 131.5, ArC;131.3, ArC; 131.0, ArCH; 130.8, ArCH; 130.2, ArCH; 129.3, ArC; 129.2,ArCH; 127.6, ArCH; 127.3, ArCH; 127.1, ArCH; 126.4, ArCH; 126.3, ArCH;126.0, ArCH; 125.5, ArCH; 125.3, ArCH; 124.8, ArCH; 122.1, ArC; 121.8,ArC; 117.0, C3′″; 117.0, ArCH; 116.2, ArCH; 70.9, C1′″; 67.4, C6′; 53.1,H3′; 52.6, OCH₃; 40.1, C3″; 30.3, C2″; 24.5, C1″. Mass Spectrum (ES,+ve) m/z 632 (100%) [M⁺]. HRMS calcd for C₃₈H₃₈N₃O₆ 632.2761, found632.2777.

Methyl(3R)-3-(6-(2-[2′-allyloxy-{1,1′}-(S)-binaphthalen-2-yloxy])-1,4-diaza-3-(3-guanidylpropyl)-2,5-dioxohexyl)benzoatehydrochloride (156)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 151 (49 mg, 0.056 mmol) to yield 156 (32mg, 0.045 mmol, 80%) as a cream solid. Mp 124-126° C. ¹H NMR (CD₃OD, 300MHz): δ 8.28 (s, 1H, ArH); 7.90 (m, 4H, ArH); 7.32 (m, 9H, ArH); 7.07(m, 2H, ArH); 5.73 (m, 1H, H2′″); 4.97 (m, 2H, H3′″); 4.52 (m, 5H, H6′,H1′″ and H3′); 3.92 (s, 3H, OCH₃); 3.01 (m, 2H, H3″); 1.63 (m, 2H, H1″);1.17 (m, 2H, H2″). ¹³C NMR (CD₃OD, 75 MHz): δ. 171.0, 1-CO; 170.4, C5′;168.0, C2′; 158.4, CN₃; 155.4, ArC; 154.2, ArC; 140.0, C2′″; 138.8, ArC;135.1, ArC; 135.0, ArC; 132.0, ArCH; 131.3, ArC; 131.1, ArC; 131.0,ArCH; 130.7, ArCH; 130.2, ArCH; 129.4, ArC; 129.3, ArCH; 127.7, ArCH;127.6, ArCH; 126.4, ArCH; 126.3, ArCH; 126.1, ArCH; 126.0, ArCH; 125.9,ArCH; 125.4, ArCH; 125.4, ArCH; 122.0, ArC; 121.9, ArC; 117.2, C3′″;117.0, ArCH; 116.4, ArCH; 70.8, C1′″; 69.4, C6′; 53.5, H3′; 52.9, OCH₃;41.8, C3″; 30.6, C2″; 25.8, C1″. Mass Spectrum (ES, +ve) m/z 698 (25%)[MNa⁺], 413 (100%). HRMS calcd for C₃₉H₄₀N₅O₆ 674.2979, found 674.2979.

Benzyl(3R)-3-(6-(2-[2′-allyloxy-{1,1′}-(S)-binaphthalen-2-yloxy])-3-(3-aminopropyl)-1,4-diaza-2,5-dioxohexyl)benzoatehydrochloride (157)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 148 (35 mg, 0.043 mmol) to yield 157 (30mg, 0.040 mmol, 93%) as a highly hydroscopic cream solid. ¹H NMR (CD₃OD,500 M) δ 8.25 (s, 1H, ArH); 7.80 (m, 7H, ArH); 7.28 (m, 11H, ArH); 5.58(m, 1H, H2′″); 5.27 (s, 2H, ArCH₂); 4.79 (m, 2H, H3′″); 4.46 (m, 5H,H6′, H1′″ and H3′); 2.68 (m, 2H, H3″); 1.59 (m, 2H, H1″); 1.22 (m, 2H,H2″). ¹³C NMR (CD₃OD, 125 MHz): δ. 171.2, 1-CO; 169.8, C5′; 167.2, C2′;153.9, ArC; 152.8, ArC; 137.2, C2′″; 136.4, ArC; 133.7, ArC; 133.6, ArC;133.1, ArCH; 131.0, ArCH; 129.2, ArC; 129.0, ArC; 128.4, ArCH; 128.2,ArCH; 128.0, ArCH; 127.0, ArCH; 126.8, ArCH; 126.6, ArCJH; 126.4, ArCH;125.2, ArCH; 126.0, ArCH; 125.6, ArCH; 125.2, ArCH; 124.4, ArCH; 123.9,ArCH; 123.0, ArC; 122.8, ArC; 121.0, ArCH; 120.8, ArCH; 119.5, ArC;117.2, ArC; 116.2, C3′″; 115.0, ArCH; 112.3, ArCH; 70.2, C1′″; 67.7,C6′; 51.2, C3′; 40.4, C3″; 32.8, C2″; 23.0, C1″. Mass Spectrum (ES, +ve)m/z 750 (35%) [MH⁺], 360 (100%). HRMS calcd for C₄H₂N₃O₆ 708.3074, found708.3062.

Benzyl(3R)-3-(6-(2-[2′-allyloxy-{1,1′}-(S)-binaphthalen-2-yloxy])-1,4-diaza-3-(3-guanidylpropyl)-2,5-dioxohexyl)benzoatehydrochloride (158)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 152 (15 mg, 0.016 mmol) to yield 158 (6mg, 0.0076 mmol, 48%) as a highly hydroscopic cream solid. ¹H NMR(CD₃OD, 500 MHz): δ 8.22 (s, 1H, ArH); 7.79 (m, 7H, ArH); 7.25 (m, 13H,ArH); 5.59 (m, 1H, H2′″); 5.27 (s, 2H, ArCH₂); 4.80 (m, 2H, H3′″); 4.47(m, 4H, H1′″ and H6′); 4.28 (dd, J=5.0, 7.0 Hz, 1H, H3′); 2.92 (m, 2H,H3″); 1.54 (m, 2H, H1″); 1.08 (m, 2H, H2″). ¹³C NMR (CDCl₃, 125 MHz): δ169.8, 1-CO; 168.9, C5′; 166.4, C2′; 153.4, ArC; 152.7, ArC; 137.5,C2′″; 136.2, ArC; 133.4, ArC; 133.3, ArC; 133.2, ArCH; 131.4, ArC;131.2, ArC; 130.5, ArCH; 130.4, ArCH; 129.7, ArCH; 129.4, ArC; 128.8,ArCH; 128.5, ArCH; 128.7, ArCH; 128.4, ArCH; 126.9, ArCH; 126.8, ArCH;126.2, ArCH; 125.9, ArCH; 125.6, ArCH; 124.8, ArCH; 124.6, ArCH; 124.5,ArCH; 121.7, ArCH; 121.2, ArC; 120.9, ArC; 119.6, ArC; 116.9, C3′″;116.5, ArCH; 114.7, ArCH; 70.2, C1′″; 68.5, C6′; 66.9, ArCH₂; 52.8, C3′;40.3, C3″; 29.8, C2″; 25.3, C1″. Mass Spectrum (ES, +ve) m/z 750 (100%)[M⁺]. HRMS calcd for C₄₅H₄₄N₅O₆ 750.3292, found 750.3273.

Allyl(3R)-3-(6-(2-[2′-allyloxy-{1,1′}-(S)-binaphthalen-2-yloxy])-3-(3-aminopropyl)-1,4-diaza-2,5-dioxohexyl)benzoatehydrochloride (159)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 149 (8 mg, 0.011 mmol) to yield 159 (7 mg,0.010 mmol, 92%) as a highly hydroscopic cream solid. ¹H NMR (CDCl₃, 300MHz): δ 8.20 (s, 1H, ArH); 7.89 (m, 7H, ArH); 7.26 (m, 8H, ArH); 6.02(m, 1H, CH-ester); 5.62 (m, 1H, H2′″); 5.34 (dd, J=1.5, 15.5 Hz, 1H,H3_(a)-ester); 5.20 (dd, J=1.5, 10.5 Hz, 1H, H3_(b)-ester); 4.83 (m, 2H,H13′″); 4.81 (m, 2H, H1-ester); 4.50 (m, 5H, H6′, H3′ and H1′″); 2.68(m, 2H, H3″); 1.59 (m, 2H, H1″); 1.12 (m, 2H, H2″). ¹³C NMR (CDCl₃, 75MHz): δ 169.5, 1-CO; 169.2, C5′; 166.0, C2′; 154.2, ArC; 152.6, ArC;138.4, ArC; 133.9, C2-ester; 133.8, C2′″; 133.7, ArC; 132.5, ArC; 131.2,ArC; 130.9, ArCH; 130.4, ArCH; 129.9, ArC; 129.7, ArC; 129.6, ArCH;128.9, ArCH; 128.4, ArCH; 128.2, ArCH; 126.9, ArCH; 126.0, ArCH; 125.8,ArCH; 125.4, ArCH; 125.3, ArCH; 124.6, ArCH; 124.5, ArCH; 124.0, ArCH;120.8, ArC; 119.8, ArC; 118.5, C3-ester; 116.8, C3′″; 116.1, ArCH;114.9, ArCH; 70.7, C1-ester; 68.7, C1′″; 66.4, C6′; 52.2, C3′; 39.3,C3″; 28.6, C2″; 26.2, C1″. Mass Spectrum (ES, +ve) m/z 698 (30%) [MH⁺],123 (100%). HRMS calcd for C₄₀H₄₀N₃O₆ 658.2917, found 658.2918.

Allyl(3R)-3-(6-(2-[2′-allyloxy-{1,1′}-(S)-binaphthalen-2-yloxy])-1,4-diaza-3-(3-guanidinopropyl)-2,5-dioxohexyl)benzoatehydrochloride (160)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 153 (40 mg, 0.044 mmol) to yield 160 (11mg, 0.015 mmol, 34%) as a highly hydroscopic cream solid. ¹H NMR (CD₃OD,500 MHz): δ 8.38 (s, 1H, ArH); 7.99 (t, J=7.5 Hz, 2H, ArH); 7.88 (t,J=7.5, 2H, ArH); 7.76 (t, J=8.0 Hz, 2H, ArH); 7.52 (d, J=9.0 Hz, 1H,ArH); 7.45 (d, J=9.0, 1H, ArH); 7.40 (t, J=8.0 Hz, 1H, ArH); 7.31 (dd,J=7.0, 14.5 Hz, 2H, ArH); 7.19 (t, J=7.0 Hz, 2H, ArH); 7.07 (m, 2H,ArH); 6.82 (d, J=8.0 Hz, 1H, NH); 6.04 (m, 1H, CH-ester); 5.70 (m, 1H,H2′″); 5.30 (m, 2H, H3-ester); 4.92 (m, 2H, H3′″); 4.53 (m, 6H, H6′,H1-ester and H1′″); 4.43 (m, 1H, H3′); 3.04 (m, 2H, H3″); 1.68 (m, 2H,H1″); 1.20 (m, 2H, H2′). ¹³C NMR (CD₃OD, 125 MHz): δ. 171.0, 1-CO;167.3, C2′; 158.4, CN₃; 155.3, ArC; 154.0, ArC; 139.9, ArC; 135.1,C2-ester; 135.0, C2′″; 134.8, ArC; 131.9, ArC; 130.9, ArCH; 130.9, ArC;130.8, ArC; 130.1, ArCH; 129.2, ArCH; 129.1, ArCH; 127.6, ArCH; 127.5,ArCH; 126.3, ArCH; 126.2, ArC; 125.8, ArCH; 125.7, ArCH; 125.7, ArCH;125.3, ArCH; 124.9, ArCH; 122.2, ArC; 122.1, ArCH; 121.8, ArCH; 120.4,ArC; 118.6, C3-ester; 117.1, C3′″; 117.0, ArCH; 116.1, ArCH; 72.4,C1-ester; 70.9, C1′″; 69.4, C6′; 66.7, ArCH₂; 53.5, C3′; 41.8, C3″;30.4, C2″; 25.6, C1″. Mass Spectrum (ES, +ve) m/z 700 (100%) [M⁺]. HRMScalcd for C₄₁H₄₂N₅O₆ 700.3135, found 700.3129.

(3R)-3-(6-(2-[2′-allyloxy-{1,1′}-(S)-binaphthalen-2-yloxy])-3-[(3-aminopropyl]-1,4-diaza-2,5-dioxohexyl)-N-benzyloxybenzamidehydrochloride (161)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 150 (73 mg, 0.089 mmol) to yield 161 (67mg, 0.088 mmol, 99%) as a hydroscopic white solid. ¹H NMR (CD₃OD, 500MHz): δδ 7.50 (m, 20H, ArH); 5.63 (m, 1H, H2′″); 4.90 (m, 2H, H3′″);4.46 (m, 6H, H6′, H1′″ and ArCH₂); 3.90 (m, 1H, H3′); 3.23 (m, 2H, H3″);1.62 (m, 2H, H1″); 1.15 (m, 2H, H2″). ¹³C NMR (CD₃OD, 75 MHz): δ 170.7,1-CO; 170.5, C5′; 167.7, C2′; 155.4, ArC; 154.0, ArC; 139.9, C2′″;137.3, ArC; 135.1, ArC; 134.9, ArC; 134.8, ArCH; 134.1, ArC; 131.6, ArC;131.0, ArCH; 130.9, ArCH; 130.8, ArCH; 130.6, ArCH; 130.4, ArCH; 130.2,ArCH; 129.6, ArCH; 129.5, ArCH; 129.3, ArCH; 129.2, ArCH; 127.8, ArCH;127.6, ArCH; 126.8, ArCH; 125.6, ArCH; 125.2, ArCH; 123.8, ArC; 121.9,ArC; 120.6, ArCH; 120.2, ArCH; 118.8, ArCH; 118.4, ArCH; 117.4, C3′″;116.6, ArC; 79.2, C1′″; 71.0, ArCH₂; 69.5, C6′; 53.2, C3′; 40.0, C3″;30.3, C2″; 24.5, C1″. Mass Spectrum (ES, +ve) m/z 723 (20%) [M⁺], 360(100%). HRMS calcd for C₄₄H₄₃N₄O₆ 723.3183, found 723.3137.

(3R)-3-(6-(2-[2′-allyloxy-{1,1′}-(S)-binaphthalen-2-yloxy])-1,4-diaza-3-[(3-guanidinopropyl]-2,5-(dioxohexyl)-N-benzyloxybenzamidehydrochloride (162)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A), from 154 (16 mg, 0.017 mmol) to yield 162 (7mg, 0.0087 mmol, 51%) as a cream solid. Mp 142° C. ¹H NMR (CD₃OD, 300MHz): δ 7.95 (m, 4H, ArH); 7.33 (m, 16H, ArH); 5.60 (m, 1H, H2′″); 4.96(m, 2H, H3′″); 4.49 (m, 6H, H6′, H1′″ and ArCH₂); 3.97 (m, 1H, H3′);3.04 (m, 2H, H3″); 1.66 (m, 2H, H1″); 1.20 (m, 2H, H2″). ¹³C NMR (CD₃OD,75 MHz): δ 172.6, 1-CO; 171.1, C5′; 167.7, C2′; 158.4, CN₃; 155.4, ArC;154.0, ArC; 139.8, C2′″; 136.8, ArC; 135.1, ArC; 135.0, ArC; 134.9,ArCH; 134.0, ArC; 131.4, ArC; 130.9, ArCH; 130.9, ArCH; 130.8, ArCH;130.4, ArCH; 130.2, ArCH; 130.0, ArCH; 129.7, ArCH; 129.5, ArCH; 129.3,ArCH; 129.2, ArCH; 127.6, ArCH; 127.5, ArCH; 126.4, ArCH; 125.9, ArCH;124.6, ArC; 123.8, ArC; 121.9, ArC; 120.4, ArCH; 120.3, ArCH; 118.8,ArCH; 118.0, ArCH; 117.0, C3′″; 116.2, ArC; 79.2, C1′″; 71.0, ArCH₂;69.4, C6′; 53.6, C3′; 41.8, C3″; 30.5, C2″; 25.7, C1″. Mass Spectrum(ES, +ve) m/z 765 (20%) [M⁺], 102 (100%). HRMS calcd for C₄₅H₄₅N₆O₆765.3401, found 765.3375.

(3R)-(3-(3-aminopropyl)-1,4-diaza-7-oxa-2,5-dioxohexyl-3-(6-(2-[2′-propyloxy-{1,1′}-(S)-binaphthalen-2-yloxy])-N-hydroxybenzamidehydrochloride (163)

To a solution of 150 (28 mg, 0.034 mmol) in THF (3 mL) was addedpalladium on activated carbon (15 mg). The resulting mixture was flushedwith hydrogen gas and allowed to stir for 16 h. The mixture was filteredthrough celite and evaporated to dryness. This intermediate product wasthen subjected to the general acid deprotection procedure (Procedure A)to yield the title compound (16 mg, 0.024 mmole, 70%) as a white solid.Mp 116° C. ¹H NMR (CD₃OD, 500 MHz): δ 7.89 (m, 5H, ArH); 7.30 (m, 9H,ArH); 4.56 (m, 2H, H6′); 4.08 (m, 1H, H3′); 3.88 (m, 2H, H1′″); 3.66 (m,2H, H3″); 1.67 (m, 2H, H1″); 1.35 (m, 4H, H2″ and H2′″); 0.76 (m, 3H,H13′″). ¹³C NMR (CD₃OD, 125 MHz): δ 170.9, 1-CO; 170.7, C5′; 166.3, C2′;155.9, ArC; 154.1, ArC; 139.7, ArC; 135.3, ArCH; 135.1, ArCH; 131.0,ArC; 130.9, ArCH; 130.7, ArCH; 130.5, ArCH; 130.4, ArC; 130.2, ArC;130.1, ArCH; 129.5, ArCH; 129.3, ArCH; 129.1, ArCH; 127.5, ArCH; 126.9,ArCH; 126.4, ArCH; 125.9, ArCH; 125.6, ArCH; 125.3, ArC; 124.7; ArC;124.5, ArC; 117.0, ArCH; 116.9, ArCH; 116.2, ArC; 72.1, C6′; 69.5, C1′″;53.1, C3′; 40.0, C3″; 30.4, C2″; 24.8, C2′″; 23.7, C1″; 10.5, C3′″. MassSpectrum (ES, +ve) m/z 636 (50%) [M⁺], 623 (100%). HRMS calcd forC₃₇H₃₉N₄O₆ 635.2870, found 635.2863.

(3R)-(1,4-diaza-3-(3-guanidinopropyl)-7-oxa-2,5-dioxohexyl-3-(6-(2-[2′-propyloxy-{1,1′}-(S)-binaphthalen-2-yloxy])-N-hydroxybenzamidehydrochloride (164)

To a solution of 154 (39 mg, 0.040 mmol) in THF (3 mL) was addedpalladium on activated carbon. The resulting mixture was flushed withhydrogen gas and allowed to stir for 16 h. The mixture was filteredthrough celite and evaporated to dryness. This intermediate product wasthen subjected to the general acid deprotection procedure (Procedure A)to yield the title compound (24 mg, 0.034 mmole, 84%) as a white solid.Mp 158-160° C. ¹H NMR (CD₃OD, 300 MHz): δ 9.96 (bs, 1H, OH); 7.95 (m,5H, ArH); 7.24 (m, 9H, ArH); 4.45 (AB_(q), J=14.1 Hz, 2H, H6′); 4.09 (m,1H, H3′); 3.92 (m, 2H, H1′″); 3.03 (m, 2H, H3″); 1.62 (m, 2H, H1″); 1.40(m, 2H, H2′″); 1.17 (m, 2H, H2″); 0.51 (t, J=7.2 Hz, 3H, H3′″). ¹³C NMR(CDCl₃, 75 MHz): δ 170.9, 1-CO; 170.8, C5′; 170.8, C2′; 158.5, CN₃;155.9, ArC; 154.0, ArC; 139.9, ArC; 135.2, ArCH; 135.1, ArCH; 131.5,ArC; 131.0, ArC; 130.9, ArCH; 130.7, ArCH; 130.2, ArC; 130.1, ArC;129.3, ArCH; 129.1, ArCH; 127.6, ArCH; 127.5, ArCH; 126.4, ArCH; 125.9,ArCH; 125.3, ArCH; 124.7, ArCH; 124.4, ArCH; 124.2, ArCH; 123.6, ArC;122.0, ArC; 120.3, ArC; 116.9, ArCH; 116.2, ArCH; 72.1, C6′; 69.4, C1′″;52.5, C3′; 41.9, C3″; 30.5, C2″; 25.7, C2′″; 23.7, C1″; 10.5, C3′″. MassSpectrum (ES, +ve) m/z 677 (100%) [M⁺]. HRMS calcd for C₃₈H₄₁N₆O₆677.3088, found 677.3130.

Methyl(2S)-3-(4-hydroxyphenyl)-2-methoxycarboxamidopropanoate (170)

To a solution of methyl(2S)-2-amino-3-(4-hydroxyphenyl)propanoatehydrochloride (189 mg, 0.82 mmol) and sodium bicarbonate (210 mg, 2.5mmol) in THF (3 mL) and water (3 mL) at 0° C. was added methylchloroformate (86 mg, 0.9 mmol) and the resulting mixture was allowed tostir for 3 h. The reaction was quenched with water (30 mL) and extractedwith EtOAc (30 mL) and DCM (2×30 mL). The combined organic fractionswere dried and evaporated to dryness to yield the title compound (195mg, 0.77 mmol, 94%) as a clear oil, which had spectral data in agreementwith that reported.¹²⁷ ¹H NMR (CDCl₃, 300 MHz): δ 6.95 (d, J=8.7 Hz, 2H,ArH2′ and ArH6′); 6.73 (d, J=8.4 Hz, 2H, ArH3′ and ArH5′); 5.31 (d,J=8.4 Hz, 1H, NH); 4.59 (m, 1H, H2); 3.71 (s, 3H, CH₃, NCOOCH₃); 3.65(s, 3H, OCH₃); 3.01 (m, 2H, C3). Mass Spectrum (ES, +ve) m/z 254 (100%)[MH⁺]. HRMS calcd for C₁₂H₁₆NO₅ 254.1029, found 254.1036.

Methyl(2S)-3-(4-allyloxyphenyl)-2-methoxycarboxamidopropanoate (171)

To a solution of 170 (195 mg, 0.77 mmol) in DMF (6 mL) was added K₂CO₃(213 mg, 1.54 mmol) and the resulting mixture was allowed to stir at RTunder N₂ for 20 min before the addition of allyl bromide (0.14 mL, 1.54mmol). After 16 h the reaction was quenched with water (30 mL) andextracted with EtOAc (3×30 mL). The combined organic fractions werewashed with water (5×30 mL) and brine (30 mL). The remaining organicfractions were dried and evaporated to dryness to yield the titlecompound (220 mg, 0.75 mmol, 98%) as a white solid. Mp 145-146° C. ¹HNMR (CDCl₃, 300 MHz): δ 7.02 (d, J=8.7 Hz, ArH2′ and ArH6′); 6.83 (d,J=8.4 Hz, ArH3′ and ArH5′); 6.04 (m, 1H, H2″); 5.40 (dd, J=1.5, 17.1 Hz,1H, H3_(a)″); 5.27 (dd, J=1.2, 10.5 Hz, 1H, H3_(b)″); 5.18 (d, J=7.5 Hz,NH); 4.60 (m, 1H, H2); 4.50 (d, J=5.1 Hz, 2H, H1″); 3.71 (s, 3H,NCOOCH₃); 3.66 (s, 3H, OCH₃); 3.03 (m, 2H, C3). Mass Spectrum (ES, +ve)m/z [MH⁺]. HRMS calcd for C₁₅H₂₀NO₅ 294.1342, found 294.1346.

(2S)-3-(4-Allyloxyphenyl)-2-methoxycarboxamidopropanoic acid (172)

To a solution of 171 (220 mg, 0.75 mmol) in THF/water (3:1, 10 mL) wasadded lithium hydroxide (63 mg, 1.50 mmol) and the resulting suspensionwas allowed to stir for 16 h. The reaction mixture was diluted withwater (30 mL) and the THF was removed by evaporation in vacuo. Theaqueous layer was washed with DCM (30 mL) to remove unreacted startingmaterial. The pH of the aqueous phase was adjusted to pH 3 with 10% HCland the resulting precipitate was extracted with DCM (3×40 mL). Thecombined organic fractions were dried, and evaporated to dryness toyield the title compound (186 mg, 0.67 mmol, 89%) as a white solid. Mp170-172° C. ¹H NMR (CDCl₃, 300 MHz): δ 9.39 (bs, 1H, COOH); 7.07 (d,J=8.7 Hz, ArH2′ and ArH6′); 6.84 (d, J=8.4 Hz, ArH3′ and ArH5′); 6.03(m, 1H, H2″); 5.39 (dd, J=1.2, 17.1 Hz, 1H, H3_(a)″); 5.27 (dd, J=1.2,10.5 Hz, 1H, H3_(b)″); 4.62 (dd, J=6.0, 13.2 Hz 1H, H2); 4.50 (d, J=5.4Hz, C1″); 3.65 (s, 3H, NCOOCH₃); 3.08 (m, 2H, H3). Mass Spectrum (CI,+ve) m/z 280 (50%) [MH⁺], 220 (100%) [MH⁺ less methoxycarbonate] HRMScalcd for C₁₄H₁₇NO₅ 279.1107, found 279.1114.

Methyl(2S)-2-benzyloxycarboxamido-4-pentenoate (173)

To a solution of methyl(2S)-2-amino-4-propenoate hydrochloride (422 mg,2.56 mmol) and NaHCO₃ (645 mg, 7.68 mmol) in THF/water (3 mL/3 mL, 1:1)was added benzyl chloroformate (482 mg, 2.82 mmol) and the mixture wasallowed to stir for 16 h. The reaction was quenched with 3% HCl (20 mL)and extracted with DCM (3×20 mL), dried and concentrated to give thetitle compound (676 mg, 2.56 mmol, 100%) as a clear oil, which hadspectral data in agreement with that reported.¹²⁸ [α]_(D) ²⁰ +9.1 (c.0.15 in CHCl₃) (lit. [α]²⁰ +6.4 (c. 1.05 in MeOH))¹²⁸ ¹H NMR (CDCl₃, 300MHz): δ 7.33 (m, 5H, ArH); 5.69 (m, 1H, H4); 5.56 (d, J=7.8 Hz, 1H, NH);5.12 (m, 4H, ArCH₂, C5); 4.47 (m, 1H, H2); 3.72 (s, 3H, OCH₃); 2.54 (m,2H, H3). Mass Spectrum (CI, +ve) m/z 264 (20%) [MH⁺], 113 (100%). HRMScalcd for C₁₄H₁₈NO₄ 264.12358, found 264.12421.

Methyl(2S,4E/Z)-2-benzyloxycarboxamido-6-phenyl-4-hexenoate (174)

To a solution of 173 (181 mg, 0.69 mmol) in DCM (13.8 mL) was addedallylbenzene (163 mg, 1.38 mmol) and Grubbs' first generation catalyst(28 mg, 0.0345 mmol). The mixture was heated at reflux for 16 h. Thesolvent was removed and the crude product purified by flash columnchromatography (4:1, hexane/EtOAc) to yield the title compound as a 1:1ratio mixture of E and Z isomers (103 mg, 0.29 mmol, 42%) as a brownoil. ¹H NMR (CDCl₃, 300 MHz): δ 7.26 (m, 10H, ArH); 5.72 (m, 1H, H4);5.42 (m, 2H, NH and H5); 5.13 (s, 2H, ArCH₂O); 5.50 (m, 1H, H2);3.74/3.71 (s, 3H, OCH₃ [E & Z]); 3.39/3.34 (d, J=357.5, 6.6 Hz, 2H, H6);2.54 (m, 2H, H3). Mass Spectrum (CI, +ve) m/z 354 (20%) [MH⁺], 263(100%). HRMS calcd for C₂₁H₂₄NO₄ 354.17053, found 354.17077.

Methyl(2S)-2-amino-6-phenylhexanoate (175)

To a solution of 174 (118 mg, 0.33 mmol) in THF (30 mL) was addedpalladium on activated carbon (62 mg, 0.029 mmol). The flask wasevacuated and twice filled with H₂ gas before stirring at RT for 16 h.The reaction mixture was filtered through celite and evaporated todryness to yield the title compound (73 mg, 0.33 mmol, 100%) as a lightbrown oil. ¹H NMR (CDCl₃, 300 MHz): δ 7.21 (m, 5H, ArH); 3.71 (m, 6H,OCH₃, NH₂ and H2); 2.60 (m, 2H, H6); 1.62 (m, 6H, H3, H4 and H5). MassSpectrum (CI, +ve) m/z 222 (30%) [MH⁺], 113 (100%). HRMS calcd forC₁₃H₂₀NO₂ 222.14940, found 222.14934.

Methyl(2S,5S)-3-aza-2-benzyl-9-(tert-butoxycarboxamido)-5-(9H-9-fluorenylmethyloxycarboxamido)-4-oxononanoate(176)

The title compound was synthesized using the general coupling procedure(Procedure B) from (1S)-2-phenyl-1-methoxycarbonylethylammonium chloride(300 mg, 1.39 mmol) and(2S)-6-tert-butoxycarboxamido-2-(9H-9-fluorenylmethyloxy)carboxamidohexanoic acid (769 mg, 1.64 mmol) to afford 176 (848 mg, 1.35 mmol, 97%)as a white solid. Mp 87-90° C. ¹H NMR (CDCl₃, 300 MHz): δ 7.75 (d, J=7.2Hz, 2H, ArH1″ and ArH8); 7.58 (d, J=7.2 Hz, 2H, ArH4″ and ArH5″); 7.39(t, J=7.2 Hz, 2H, ArH3″ and ArH6); 7.30 (t, J=6.9 Hz, 2H, ArH2″ andArH7″); 7.21 (m, 2H, ArH3′ and ArH5′); 7.07 (m, 1H, ArH4′); 6.61 (d,J=7.2 Hz, 1H, NH); 5.56 (d, J=8.4 Hz, 1H, NH); 4.85 (dd, J=6.3, 14.1 Hz,1H, H2); 5.69 (bs, 1H, NH); 4.36 (m, 2H, OCH ₂—H9″); 4.19 (m, 2H, H5 andH9″); 3.69 (s, 3H, OCH₃); 3.09 (m, 2H, H2-CH ₂); 3.04 (m, 2H, H9); 1.77(m, 2H, H7); 1.63 (m, 2H, H6); 1.42 (s, 9H, C(CH₃)₃); 1.33 (m, 2H, H8).Mass Spectrum (ES, +ve) m/z 630 (10%) [MH⁺], 104 (100%). HRMS calcd forC₃₆H₄₄N₃O₇ 630.3179, found 630.3189.

Methyl(2S,5S)-3-aza-9-(tert-butoxycarboxamido)-5-(9H-9-fluorenylmethyloxycarboxamido)-4-oxo-3-(4′-phenylbutyl)nonanoate(177)

The title compound was synthesized using the general coupling procedure(Procedure B) from 175 (63 mg, 0.29 mmol) and(2S)-6-tert-butoxycarboxamido-2-(9H-9-fluorenylmethyloxy)carboxamidohexanoic acid (113 mg, 0.24 mmol) to afford 177 (138 mg, 0.21 mmol, 86%)as a clear oil. ¹H NMR (CDCl₃, 300 MHz): δ 7.73 (d, J=7.2 Hz, 2H, ArH1′″and ArH8′″); 7.57 (d, J=5.4 Hz, 2H, ArH4′″ and ArH5′″); 7.37 (t, J=7.8Hz, 2H, ArH3′″ and ArH6″″); 7.19 (m, 7H, ArH2′″, ArH7′″, ArH1″, ArH2″,ArH3″, ArH4″, ArH5″ and ArH6); 6.80 (d, J=7.2 Hz, 1H, NH); 5.71 (d,J=7.8 Hz, 1H, NH); 4.78 (bs, 1H, NH); 4.55 (m, 1H, H2); 4.37 (d, J=6.9Hz, 2H, OCH ₂-H9′″); 4.20 (m, 2H, H5 and H19′″); 3.69 (s, 3H, OCH₃);3.07 (m, 2H, H9); 2.53 (t, J=7.8 Hz, 2H, H4′); 1.84 (m, 2H, H7); 1.62(m, 2H, H6); 1.42 (s, 9H, C(CH ₂)₃); 1.36 (m, 2H, H8); 1.26 (m, 4H, H2′and H3′). Mass Spectrum (ES, +ve) m/z 673 (100%) [MH⁺]. HRMS calcd forC₃₉H₅₀N₃O₇ 672.3649, found 672.3624.

Methyl(2S,5S)-5-amino-3-aza-2-benzyl-9-(tert-butoxycarboxamido)-4-oxononanoate(178)

The title compound was synthesized using the general N-Fmoc deprotectingprocedure (Procedure C) from 176 (836 mg, 1.33 mmol) to afford 178 (142mg, 0.35 mmol, 26%) as a clear oil. ¹H NMR (CDCl₃, 300 MHz): δ 7.66 (d,J=7.8 Hz, 1H, NH); 7.22 (m, 3H, ArH3′, ArH4′ and ArH5′); 7.10 (m, 2H,ArH2′ and ArH6′); 4.83 (m, 1H, H2); 4.60 (bs, 1H, NH); 3.69 (s, 3H,OCH₃); 3.29 (dd, J=4.5, 7.5 Hz, 1H, H5); 3.08 (m, 2H, H2-CH ₂); 3.06 (m,2H, H9); 1.67 (m, 2H, H7); 1.46 (m, 2H, H6); 1.41 (s, 9H, C(CH₃)₃); 1.24(m, 2H, H8). Mass Spectrum (ES, +ve) m/z 409 (100%) [MH⁺].

Methyl(2S,5S)-2-amino-3-aza-9-(tert-butoxycarboxamido)-4-oxo-2-(4-phenylbutyl)nonanoate(179)

The title compound was synthesized using the general N-Fmoc deprotectingprocedure (Procedure C) from 177 (138 mg, 0.21 mmol) to afford 179 (78mg, 0.17 mmol, 81%) as a light brown oil. ¹H NMR (CDCl₃, 300 MHz): δ7.67 (d, J=8.1 Hz, 1H, NH); 7.22 (m, 5H, ArH); 4.56 (m, 2H, H2 and H5);3.72 (s, 3H, OCH₃); 3.11 (m, 2H, H9); 2.60 (t, J=7.5 Hz, 2H, H4′); 1.83(m, 2H, H7); 1.66 (m, 6H, H1′, H2′ and H3′); 1.44 (s, 9H, C(CH ₂)₃);1.29 (m, 2H, H8); 0.86 (m, 2H, H6). Mass Spectrum (ES, +ve) m/z 450(100%) [MH⁺]. HRMS calcd for C₂₄H₄₀N₃O₅ 450.2968, found 450.2950.

Methyl(2S,5S,8S)-8-(4-allyloxybenzyl)-3,6,9-triaza-2-benzyl-5-(4-[tert-butoxycarboxamido]butyl)-4,7,10-trioxoundecanoate(180)

The title compound was synthesized using the general peptide couplingprocedure (Procedure B) from 16 (76 mg, 0.29 mmol) and 178 (142 mg, 0.35mmol) to afford 180 (135 mg, 0.21 mmol, 72%) as an off-white solid. Mp122-126° C. ¹H NMR (CDCl₃, 300 MHz): δ 7.24 (m, 3H, ArH3′, ArH4′ andArH5′); 7.12 (m, 2H, ArH2′ and ArH6′); 7.05 (d, J=8.7 Hz, 2H, ArH2′″ andArH6′″; 6.79 (d, J=8.4 Hz, 1H, ArH3′″ and ArH5′″; 6.50 (d, J=6.9 Hz, 1H,NH); 6.01 (m, 1H, H2″″); 5.37 (dd, J=1.5, 17.1 Hz, 1H, H3_(a)″″); 5.25,J=1.2, 10.5 Hz, 1H, H3_(b)″″); 4.87 (bs, 1H, NH); 4.79 (m, 1H, H2); 4.68(m, 1H, H5); 4.45 (d, J=5.1 Hz, 2H, H1″″); 4.43 (m, 1H, H8); 3.69 (s,3H, OCH₃); 3.06 (m, 4H, 2-CH₂ and 8-CH₂); 2.93 (m, 2H, H4″); 1.95 (s,3H, H11); 1.75 (m, 2H, H2″); 1.55 (m, 2H, H1″); 1.32 (s, 9H, C(CH ₃)₃);1.26 (m, 2H, H3″). Mass Spectrum (ES, +ve) m/z 653 (10%) [MH⁺]; 104(100%). HRMS calcd for C₃₅H₄₈N₄O₈Na 675.3370, found 675.3358.

Methyl(2S,5S,8S)-2-allyl-8-(4-allyloxybenzyl)-3,6,9-triaza-5-(4-[tert-butoxycarboxamido]butyl)-11-oxa-4,7,10-trioxododecanoate(181)

The title compound was synthesized using the general peptide couplingprocedure (Procedure B) from 24 (340 mg, 0.95 mmol) and 172 (148 mg,0.53 mmol) to afford 181 (264 mg, 0.43 mmol, 81%) as an off-white solid.Mp 90-91° C. ¹H NMR (CDCl₃, 300 MHz): δ 7.08 (d, J=9.0 Hz, 2H, ArH2′″and ArH6′″); 7.00 (d, J=7.5 Hz, 1H, NH); 6.81 (d, J=8.7 Hz, 2H, ArH3′″and ArH5′″); 6.03 (m, 1H, H2″″); 5.63 (m, 1H, H2′); 5.39 (dd, J=1.5,17.1 Hz, 1H, H3_(a)″″); 5.27 (dd, J=1.5, 10.8 Hz, 1H, H3_(b)″″); 5.12(m, 2H, H3′); 4.93 (bs, 1H, NH); 4.61 (m, 1H, H2); 4.51 (m, 2H, H5 andH8); 4.49 (d, J=5.1 Hz, 2H, H1″″); 3.74 (s, 3H, NCOOCH ₃); 3.62 (s, 3H,OCH₃); 3.00 (m, 4H, H4″ and ArCH₂); 2.51 (m, 2H, H1′); 1.80 (m, 2H,H2″); 1.60 (m, 2H, H1″); 1.43 (s, 9H, C(CH ₃)₃); 1.28 (m, 2H, H3″). MassSpectrum (ES, +ve) 7m/z 619 (60%) [M⁺]; 641 (100%) [M⁺+Na]. HRMS calcdfor C₃₁H₄₆N₄O₉Na 641.3162, found 641.3184.

Methyl(2S,5S,8S)-8-(4-allyloxybenzyl)-3,6,9-triaza-5-(4-[tert-butoxycarboxamido]butyl)-4,7,10-trioxo-2-(4-phenylbutyl)undecanoate(182)

The title compound was synthesized using the general peptide couplingprocedure (Procedure B) from 16 (37 mg, 0.14 mmol) and 179 (78 mg, 0.17mmol) to afford 182 (72 mg, 0.10 mmol, 74%) as an off-white solid. Mp112-117° C. ¹H NMR (CDCl₃, 300 MHz): δ 7.20 (m, 5H, ArH); 7.09 (d, J=8.4Hz, 2H, ArH2″″ and ArH6″″); 6.82 (d, J=8.7 Hz, 2H, ArH3″″ and ArH5″″);6.45 (m, 2H, NH); 6.09 (m, 1H, NH); 6.02 (m, 1H, H2′″″); 5.39 (dd,J=1.5, 17.1 Hz, 1H, H3_(a)′″″); 5.27 (dd, J 1.5, 10.5 Hz, 1H,H3_(b)′″″); 4.79 (bs, 1H, NH); 4.60 (m, 1H, H2); 4.48 (m, 3H, H5 andH1′″″); 4.35 (m, 1H, H8); 3.72 (s, 3H, OCH₃); 3.02 (m, 4H, H4′″, 8-CH₂);2.60 (t, J=8.1 Hz, 2H, H4′); 1.97 (s, 3H, H11); 1.84 (m, 2H, H2′″); 1.66(m, 6H, H1′, H2′ and H3′); 1.43 (s, 9H, C(CH ₃)₃); 1.32 (m, 4H, H1′″ andH3)′. Mass Spectrum (ES, +ve) m/z 695 (100%) [MH⁺]. HRMS calcd forC₃₈H₅₅N₄O₈ 695.4020, found 695.4008.

Methyl(2S,5S,8S)-8-(4-allyloxybenzyl)-3,6,9-triaza-2-benzyl-5-(4[{di-tert-butoxycarbonyl}guanidino]butyl)-4,7,10-trioxoundecanoate(183)

To a solution of 180 (125 mg, 1.19 mmol) in DCM (2 mL) was added TFA (2mL) and the resulting mixture was allowed to stir for 3 h. The solventwas removed by evaporation and the oily intermediate was precipitated bythe addition of diethyl ether (5 mL) which was decanted and the solidproduct was dried in vacuo. To the salt was addedN1-tert-butoxycarboxamido(trifluoromethylsulfonylimino)methylpropanamide (82 mg, 0.21 mmol), triethylamine (0.1 mL) and DCM (3 mL).The resulting solution was allowed to stir for 16 h under N₂. Thesolvent was removed by evaporation in vacuo, and the crude product waspurified by flash chromatography (20:1, DCM/MeOH) to yield the titlecompound (177 mg, 0.21 mmol, 100%) as an off white solid. Mp 228° C. ¹HNMR (CDCl₃, 300 MHz): δ 7.26 (m, 3H, ArH3′, ArH4′ and ArH5′); 7.08 (m,4H, ArH2′, ArH6′, ArH2′″ and ArH6′″); 6.81 (d, J=8.7 Hz, 2H, ArH3′″ andArH5′″); 6.46 (t, J=8.4 Hz, 2H, NH); 6.21 (d, J=7.8 Hz, 1H, NH); 6.00(m, 1H, H2″″); 5.37 (dd, J=1.2, 16.8 Hz, 1H, H3_(a)″″); 5.26 (dd, J=1.5,10.8 Hz, 1H, H3_(b)″″); 4.78 (m, 1H, H2); 4.61 (m, 1H, H5); 4.47 (d,J=5.4 Hz, 2H, H1″″); 4.32 (m, 1H, H8); 3.71 (s, 3H, OCH₃); 3.31 (m, 2H,2-CH₂); 3.08 (m, 2H, 8-CH₂); 2.97 (d, J=6.9 Hz, 2H, H4″); 1.98 (s, 3H,H11); 1.76 (m, 2H, H2″); 1.52 (m, 2H, H1″); 1.48 (s, 18H, C(CH₃)₃); 1.25(m, 2H, H3″). Mass Spectrum (ES, +ve) m/z 795 (20%) [MH⁺]; 104 (100%).HRMS calcd for C₄₁H₅₉N₆O₁₀ 795.4293, found 795.4310.

Methyl(2S,5S,8S)-8-(4-allyloxybenzyl)-3,6,9-triaza-2-benzyl-5-(4-guanidinobutyl)-4,7,10-trioxoundecanoatehydrochloride (165)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A) from 183 (157 mg, 0.20 mmol) to yield 165 (93mg, 0.15 mmol, 74%) as a white solid. Mp 175-179° C. ¹H NMR (CD₃OD, 300MHz): δ 7.20 (m, 5H, ArH′); 7.11 (d, J=8.1 Hz, 2H, ArH2′″ and ArH6′″);6.78 (d, J=8.4 Hz, 2H, ArH3′″ and ArH5′″; 6.01 (m, 1H, H2″″); 5.35 (dd,J=1.2, 16.8 Hz, 1H, H3_(a)″″); 5.20, J=1.5, 10.8 Hz, 1H, H3_(b)″″); 4.60(dd, J=5.7, 8.1 Hz, 1H, H2); 4.45 (m, 1H, H5); 4.47 (d, J=5.4 Hz, 2H,H1″″); 4.34 (dd, J=4.8, 8.4 Hz, 1H, H8); 3.65 (s, 3H, OCH₃); 3.05 (m,4H, 2-CH₂ and 8-CH₂); 2.77 (m, 2H, H4″); 1.90 (s, 3H, H111); 1.73 (m,2H, H2″); 1.56 (m, 2H, H1″); 1.37 (m, 2H, H3″). ¹³C NMR (CD₃OD, 75 MHz):δ 173.6, C7; 173.4, C4; 173.3, C2; 173.0, C10; 158.7, CN₃; 158.4,ArC4′″; 137.8, ArCH2′ and ArCH6′; 134.8, C2″″; 131.0, ArCH2′″ andArC6′″; 130.3, ArC1′″; 130.1, ArCH4′; 129.4, ArC1′; 127.8, ArCH3′ andArCH5′; 117.2, C3″″; 115.6, ArCH3′″ and ArCH5′″; 69.7 C1″″; 56.6, C2;55.2, C5; 54.0, OCH₃; 52.7, C8; 42.2, C4″; 38.3, 2-CH₂; 37.8, 8-CH₂;32.6, C1″; 28.2, C3″; 23.6, C11; 22.5, C2″. Mass Spectrum (ES, +ve) m/z596 (100%) [MH⁺]. HRMS calcd for C₃₁H₄₃N₆O₆ 595.3244, found 595.3225.

Methyl(2S,5S,8S)-2-allyl-8-(4-allyloxybenzyl)-3,6,9-triaza-5-(4-{[di-tert-butoxycarbonyl]guanidino}butyl)-11-oxa-4,7,10-trioxododecanoate(184)

To a solution of 181 (250 mg, 0.40 mmol) in DCM (3 mL) was added TFA (3mL) and the resulting mixture was allowed to stir for 3 h. The solventwas removed by evaporation in vacuo, and the oily intermediate wasprecipitated by the addition of diethyl ether (5 mL) which was decantedand the solid product was dried in vacuo. To the remaining salt wasadded N1-tert-butoxycarboxamido(trifluoromethylsulfonylimino)methylpropanamide (172 mg, 0.44 mmol), triethylamine (0.5 mL) and DCM (3 mL).The resulting solution was allowed to stir for 16 h under N₂. Thesolvent was removed and the crude product was purified by flashchromatography (20:1, DCM/MeOH) to yield the title compound (309 mg,0.40 mmol, 100%) as an off white oil. ¹H NMR (CDCl₃, 300 MHz): δ 8.33(bs, 1H, NH); 7.08 (d, J=8.7 Hz, 2H, ArH2′″ and ArH6′″); 6.83 (d, J=8.7Hz, 2H, ArH3′″ and ArH5′″); 6.69 (t, J=6 Hz, 2H, NH); 6.03 (m, 1H,H2″″); 5.67 (m, 1H, H2′); 5.40 (dd, J=1.2, 17.1 Hz, 1H, H3_(a)″″); 5.33(d, J=7.8 Hz, 1H, NH); 5.27 (m, J=1.5, 10.5 Hz, 1H, H3_(b)″″); 5.12 (m,2H, H3′); 4.57 (m, 1H, H2); 4.50 (d, J=5.1 Hz, 2H, H1″″); 4.40 (m, 2H,H5 and H8); 3.74 (s, 3H, H12); 3.62 (s, 3H, OCH₃); 3.35 (t, J=6.0 Hz,2H, H4″); 2.99 (m, 2H, ArCH₂); 2.52 (m, 2H, H1′); 1.83 (m, 2H, H2″);1.57 (m, 2H, H1″); 1.48 (s, 18H, C(CH ₃)₃); 1.32 (m, 2H, H3″). MassSpectrum (ES, +ve) m/z 761 (100%) [MH⁺]. HRMS calcd for C₃₇H₅₇N₆O₁,761.4085, found 761.4067.

Methyl(2S,5S,8S)-2-allyl-8-(4-allyloxybenzyl)-3,6,9-triaza-5-(4-{guanidino}butyl)-11-oxo-4,7,10-trioxododecanoatehydrochloride (166)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A) from 184 (290 mg, 0.38 mmol) to yield 166 (171mg, 0.29 mmol, 76%) as a highly hydroscopic white solid. ¹H NMR (CD₃OD,300 MHz): δ 8.24 (d, J=7.2 Hz, 1H, NH); 8.09 (d, J=7.8 Hz, 1H, NH); 7.13(d, J=8.7 Hz, 2H, ArH2′″ and ArH6″); 6.82 (d, J=8.7 Hz, 2H, ArH3′″ andArH5′″); 6.03 (m, 1H, H2″″); 5.77 (m, 1H, H2′); 5.37 (dd, J=1.8, 17.4Hz, 1H, H3_(a)″″); 5.22 (dd, J=1.5, 10.5 Hz, 1H, H3_(b)″″); 5.11 (m, 2H,H3′); 4.50 (d, J=5.1 Hz, 2H, H1″″); 4.42 (m, 2H, H5 and H8); 4.31 (dd,J=5.4, 9.0 Hz, 1H, H2); 3.70 (s, 3H, H12); 3.58 (s, 3H, OCH₃); 3.17 (t,J=6.9 Hz, 2H, H4″); 2.91 (m, 2H, ArCH₂); 2.52 (m, 2H, H1′); 1.82 (m, 2H,H2″); 1.62 (m, 2H, H1″); 1.43 (m, 2H, H3″). ¹³C NMR (CD₃OD, 75 MHz): δ174.0, C7; 173.6, C1; 172.9, C4; 158.5, CN₃; 158.2, ArC4′″; 158.2, C12;134.7, C2′; 133.9, C2″″; 131.1, ArCH2′″ and ArCH6′″; 130.3, ArC1′″;118.9, C3′; 117.3, C3″″; 114.5, ArCH3′″ and ArCH5′″; 69.6, C1″″; 57.9,C8; 54.2, C5; 53.6, C2; 52.8, OCH₃; 42.3, C12; 38.2, C4″; 36.6, ArCH₂;32.7, C1′; 29.2, C1″; 23.6, C3″; 15.5, C2″. Mass Spectrum (ES, +ve) m/z658 (100%) [MH⁺ less Cl⁻]. HRMS calcd for C₂₇H₄₁N₆O₇ 561.3037, found561.3016.

Methyl(2S,5S,8S)-8-(4-allyloxybenzyl)-3,6,9-triaza-5-(4-[{di-tert-butoxycarbonyl}guanidino]butyl)-4,7,10-trioxo-2-(4-phenylbutyl)undecanoate(185)

To a solution of 182 (40 mg, 0.058 mmol) in DCM (2 mL) was added TFA (2mL) and the resulting mixture was allowed to stir for 3 h. The solventwas removed and the oily intermediate was solidified upon the additionof diethyl ether (5 mL) which was decanted and the solid product wasdried in vacuo. To the remaining salt was addedN1-tert-butoxycarboxamido(trifluoromethylsulfonylimino)methylpropanamide (34 mg, 0.086 mmol), triethylamine (0.1 mL) and DCM (2 mL).The resulting solution was allowed to stir for 16 h under N₂. Thesolvent was removed and the crude product was purified by flashchromatography (20:1, DCM/MeOH) to yield the title compound (46 mg,0.054 mmol, 95%) as an off white solid. Mp 198° C. ¹H NMR (CDCl₃, 300MHz): δ 7.20 (m, 5H, ArH); 7.08 (d, J=8.4 Hz, 2H, ArH2″″ and ArH6″″;6.81 (d, J=8.4 Hz, 2H, ArH3″″ and ArH5″″); 6.71 (d, J=7.8 Hz, 1H, NH);6.45 (d, J=7.8 Hz, 1H, NH); 6.02 (m, 1H, H2′″″); 5.38 (dd, J=1.5, 17.4Hz, 1H, H3_(z)″″); 5.26 (dd, J 1.2, 10.5 Hz, 1H, H3_(b)′″″); 4.65 (m,1H, H2); 4.47 (d, J=5.1 Hz, 2H, H1′″″); 4.40 (m, 2H, H5 and H8); 3.97(s, 1H, NH); 3.71 (s, 3H, OCH₃); 3.37 (bs, 2H, H4′″); 2.98 (m, 2H,8-CH₂); 2.59 (t, J=7.8 Hz, 2H, H4′); 1.96 (s, 3H, C11); 1.84 (m, 2H,H2′″); 1.63 (m, 6H, H1′, H2′ and H3′); 1.49 (s, 18H, C(CH ₃)₃); 1.36 (m,4H, H1′″ and H3). Mass Spectrum (ES, +ve) m/z 837 (100%) [MH⁺]. HRMScalcd for C₄₄H₆₅N₆O₁₀ 837.4762, found 837.4744.

Methyl(2S,5S,8S)-8-(4-allyloxybenzyl)-3,6,9-triaza-5-(4-guanidinobutyl)-4,7,10-trioxo-2-(4-phenylbutyl)undecanoatehydrochloride (167)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A) from 185 (40 mg, 0.048 mmol) to yield 167 (18mg, 0.026 mmol, 56%) as a white solid. Mp 180-188° C. ¹H NMR (CD₃OD, 300MHz) δ 8.23 (d, J=7.2 Hz, 1H, NH); 8.08 (d, J=7.2 Hz, 1H, NH); 7.15 (m,7H, ArH); 6.81 (d, J=8.7 Hz, 2H, ArH3″″ and ArH5″″); 6.02 (m, 1H,H12′″″); 5.36 (dd, J=1.5, 17.1 Hz, 1H, H3_(a)′″″); 5.21 (dd, J=1.5, 10.5Hz, 1H, H3_(b)′″″); 4.49 (m, 3H, H2 and H′″″); 4.36 (m, 2H, H5 and H8);3.68 (s, 3H, OCH₃); 3.16 (m, 2H, H4′″); 2.92 (m, 2H, 8-CH₂); 2.60 (t,J=7.2 Hz, 2H, H4′); 1.91 (s, 3H, H11); 1.82 (m, 2H, H2′″); 1.61 (m, 8H,H1′, H2′, H3′ and H1′″); 1.42 (m, 2H, H3). ¹³C NMR (CD₃OD, 75 MHz): δ174.1, C7; 173.9, C4; 174.4, C1; 159.0, C10; 158.6, CN₃; 143.5, ArC4″″;135.0, ArC1″; 131.2, C2′″″; 130.4, ArC1″″; 129.4, ArCH2″″ and ArCH6″″;129.3, ArCH3″ and ArCH5″; 126.8, ArCH4″; 117.4, C3′″″; 115.7, ArCH3″″and ArCH5″″; 69.7, C1′″″; 56.6, C5; 53.9, C2; 53.7, OCH₃; 52.7, C8;42.3, C4′″; 37.9, 8-CH₂; 36.6, C4′; 32.7, C1′; 32.2, C3′; 32.1, C1′″;29.2, C3′″; 26.4, C11; 23.6, C2′; 22.4, C2′″. Mass Spectrum (ES, +ve)m/z 638 (100%) [M⁺]. HRMS calcd for C₃₄H₄₉N₆O₆₅ 637.3714, found637.3745.

Di-tert-butyl N-3-butenyliminodicarboxylate (186)

To a solution of di-tert-butyliminodicarboxylate (868 mg, 4 mmol),cesium carbonate (2.61 g, 8 mmol), and lithium iodide (28 mg, 0.2 mmol)in 2-butanone (20 mL) was added 4-bromobutene (812 mg, 6 mmol) and themixture was heated at reflux for 48 h. The reaction was allowed to cooland was quenched with brine (40 mL) and extracted with diethyl ether(3×20 mL). The combined organic fractions were washed with brine (30mL), dried, and evaporated to yield the title compound (1.01 g, 3.7mmol, 93%) as a light brown oil. ¹H NMR (CDCl₃, 300 MHz): δ 5.77 (m, 1H,H3); 5.04 (m, 2H, H4); 3.62 (dd, J=6.0, 8.7 Hz, 2H, H1); 2.30 (m, 2H,H2); 1.51 (s, 18H, 2×(CH₃)₃). Mass Spectrum (ES, +ve) m/z 310 (55%)[MH⁺], 294 (30%) [MNa⁺], 272 (40%) [MH⁺]. HRMS calcd for C₁₄H₂₆NO₄272.1862, found 272.1848.

tert-Butyl N-3-butenylcarbamate (187)

To a solution of 186 (708 mg, 2.60 mmol) in DCM (20 mL) was addedtrifluoroacetic acid (593 mg, 5.20 mmol) and the mixture was allowed tostir for 5 min before being quenched with 2M NaOH (25 mL) and extractedwith DCM (3×20 mL). The combined organic fractions were dried, andconcentrated to yield the title compound (429 mg, 2.50 mmol, 96%) as alight brown oil, which had spectral data in agreement with thatreported.¹⁰⁴ ¹H NMR (CDCl₃, 300 MHz): δ 5.75 (m, 1H, H3); 5.08 (m, 2H,H4); 4.59 (bs, 1H, NH); 3.20 (dd, J=6.3, 12.6 Hz, 2H, H1); 2.24 (dd,J=6.9, 12.6 Hz, 2H, H2); 1.44 (s, 9H, (CH₃)₃). Mass Spectrum (ES, +ve)m/z 116 (100%) [MH⁺ less 56 (Boc rearrangement].

Methyl(2S,4E/Z)-2-(benzyloxycarboxamido)-7-(tert-butoxycarboxamido)-4-heptenoate(188)

To a solution of 187 (220 mg, 1.29 mmol) in DCM (13 mL) was added 173(169 mg, 0.64 mmol) and Grubbs' first generation catalyst (53 mg, 0.064mmol). The mixture was heated at reflux under N₂ for 16 h. The solventwas removed and the crude product purified by flash columnchromatography (6:1, hexane/EtOAc) to yield the title compound (180 mg,0.44 mmol, 69%) as a brown oil as a 1:1 mixture of E and Z isomers.[α]_(D) ²⁴ −34.6 (c. 0.3 in EtOH). ¹H NMR (CDCl₃, 300 MHz): δ 7.35 (m,5H, ArH); 5.43 (m, 3H, H4, H5, NH); 5.11/5.10 (s, 2H, OCH₂Ph[E and Z]);4.61 (bs, 1H, NH); 4.43 (m, 1H, H2); 3.75/3, 72 (s, 3H, OCH₃[E and Z]);3.11 (m, 2H, H7); 2.47 (m, 2H, H3); 2.17 (m, 2H, H6); 1.43 (s, 9H,(CH₃)₃). Mass Spectrum (ES, +ve) m/z 429 (100%) [MNa⁺], 407 (20%) [MH⁺].HRMS calcd for C₂₁H₃₁N₂O₆ 407.2182, found 407.2171.

Methyl(2S)-2-amino-7-(tert-butoxycarboxamido)-4-heptanoate (189)

To a solution of 188 (25 mg, 0.061 mmol) in THF (4 mL) was addedpalladium on activated carbon (13 mg, 0.0061 mmol) The reaction vesselwas evacuated, flushed with H2 and allowed to stir for 16 h. Theresulting crude product was filtered through celite and evaporated toyield the title compound (15 mg, 0.055 mmol, 90%) as a clear oil.[α]_(D) ²⁴ +9.6 (c. 0.1 in EtOH). ¹H NMR (CDCl₃, 300 MHz): δ 4.55 (bs,1H, NH); 3.72 (s, 3H, OCH₃); 3.44 (t, J=6.0 Hz, 1H, H2); 3.10 (m, 2H,H7); 1.86 (m, 4H, H3, H4); 1.44 (s, 9H, (CH₃)₃); 1.37 (m, 4H, H5, H6).Mass Spectrum (ES, +ve) m/z 275 (90%) [MH⁺]; 219 (100%). HRMS calcd forC₁₃H₂₇N₂O₄ 275.1971, found 275.1967.

(2S)-2,7-Diaminoheptanoic acid dihydrochloride (193)

A solution of 189 (16 mg, 0.058 mmol) in 10M HCl (3 mL) was allowed tostir for 48 h. The product was isolated by evaporation and dried overP₂O₅ to yield the title compound (14 mg, 0.058 mmol, 100%) as ahydroscopic white solid, which had spectral data in agreement with thatreported.¹⁰⁶ [α]_(D) ²² +10.9 (c. 0.1 in HCl) (Lit. [α]_(D) ²³+14.4)¹⁰⁶¹H NMR (D₂O, 300 MHz): δ 3.90 (t, J=6.3 Hz, 1H, H2); 2.83 (t, J=7.5 Hz,2H, H7); 1.81 (m, 2H, H3); 1.64 (m, 2H, H5); 1.52 (m, 2H, H6); 1.30 (m,2H, H4). Mass Spectrum (ES, +ve) m/z 161 (100%) [M²⁺]. HRMS calcd forC₇H₁₇N₂O₂ 161.1290, found 161.1294.

Methyl(2S,5S)-5-(4-allyloxybenzyl)-3,6-diaza-2-(5-[tert-butoxycarboxamido]pentyl)-4,7-dioxooctanoate(190)

The title compound was synthesized using the general peptide couplingprocedure (Procedure B) from 16 (53 mg, 0.20 mmol) and 189 (65 mg, 0.24mmol) to afford 190 (103 mg, 0.20 mmol, 100%) as an off-white solid. Mp96-103° C. ¹H NMR (CDCl₃, 300 MHz): δ 7.11 (d, J=8.7 Hz, 2H, ArH2″ andArH6″); 6.82 (d, J=8.7 Hz, 2H, ArH3″ and ArH5″); 6.50 (d, J=7.8 Hz, 1H,NH); 6.03 (m, 1H, H2′″); 5.39 (dd, J=1.8, 17.4 Hz, 1H, H3_(a)′″); 5.26(dd, J=1.8, 9.3 Hz, 1H, H3_(b)′″); 4.66 (m, 2H, H2 and H5); 4.48 (m, 2H,H1′″); 3.69 (s, 3H, OCH₃); 2.98 (m, 4H, H5′ and ArCH₂); 1.96 (s, 3H,H8); 1.75 (m, 2H, H1′); 1.64 (m, 2H, H3′); 1.43 (s, 9H, C(CH₃)₃); 1.26(m, 4H, H2′ and H4′). Mass Spectrum (ES, +ve) m/z 520 (100%) [MH⁺]. HRMScalcd for C₂₇H₄₁N₃O₇ 542.2842, found 542.2855.

(2S,5S)-5-(4-Allyloxybenzyl)-3,6-diaza-2-(5-[tert-butoxycarboxamido]pentyl)-4,7-dioxooctanoicacid (191)

To a solution of 190 (70 mg, 0.13 mmol) in THF/water, 3:1 (8 mL) wasadded lithium hydroxide monohydrate (11 mg, 0.26 mmol) and the resultingsuspension was allowed to stir for 16 h. The reaction mixture wasdiluted with water (30 mL) and the THF was removed by evaporation. Theaqueous layer was extracted with DCM (40 mL) to remove unreactedstarting material. The aqueous phase was acidified with 10% HCl and theresulting precipitate was extracted with DCM (3×40 mL). The combinedorganic fractions were dried and evaporated to yield the title compound(39 mg, 0.08 mmol, 62%) as a clear oil. ¹H NMR (CDCl₃, 300 MHz): δ 7.09(d, J=8.7 Hz, 2H, ArH2″ and ArH6″); 6.82 (d, J=8.7 Hz, 2H, ArH3″ andArH5″); 6.05 (m, 1H, H12′″); 5.39 (dd, J=1.8, 17.4 Hz, 1H, H3_(a)′″);5.25 (dd, J=1.8, 9.3 Hz, ¹H, H3_(b)′″); 4.63 (t, J=6.9 Hz, 1H, H2); 4.47(m, 3H, H1′″ and H5); 3.05 (m, 4H, H5′ and ArCH₂); 1.95 (s, 3H, H8);1.84 (m, 2H, H1′); 1.69 (m, 2H, H3′); 1.44 (s, 9H, C(CH₃)₃); 1.28 (m,4H, H2′ and H4′).

Methyl(2S,5S,8S)-2-allyl-8-(4-allyloxybenzyl)-3,6,9-triaza-5-(4-[tert-butoxycarboxamido]pentyl)-4,7,10-trioxoundecanoate(192)

The title compound was synthesized using the general peptide couplingprocedure (Procedure B) from 18 (14 mg, 0.084 mmol) and 191 (35 mg, 0.07mmol) to afford 192 (31 mg, 0.048 mmol, 69%) as an off-white solid. Mp130-136° C. ¹H NMR (CDCl₃, 300 MHz): δ 7.07 (d, J=8.7 Hz, 2H, ArH2′″ andArH6′″); 6.80 (d, J=8.7 Hz, 2H, ArH3′″ and ArH5′″); 6.59 (d, J=8.1 Hz,1H, NH); 6.49 (d, J=7.2 Hz, 1H, NH); 6.43 (d, J=7.5 Hgz, 1H, NH); 6.02(m, 1H, H2″″); 5.67 (m, 1H, H2′); 5.39 (dd, J=1.5, 17.4 Hz, 1H,H3_(a)″″); 5.26 (dd, 1.5, 10.5 Hz, 1H, H3_(b)″″); 5.10 (m, 2H, H3′);4.70 (m, 1H, H2); 4.58 (m, 1H, H5); 4.48 (m, 2H, H1″″); 4.41 (m, 1H,H8); 3.73 (s, 3H, OCH₃); 3.04 (m, 2H, H5″); 2.98 (t, J=6.0 Hz, 2H,ArCH₂); 2.53 (m, 2H, H1′); 1.96 (s, 3H, H11); 1.76 (m, 2H, H1″); 1.58(m, 2H, H3″); 1.43 (s, 9H, C(CH₃)₃); 1.28 (m, 4H, H2″ and H4″). MassSpectrum (ES, +ve) m/z 639 (100%) [MNa⁺], 617 (10%) [MH⁺], 517 (95%)[MH⁺ less Boc]. HRMS calcd for C₃₂H₄₉N₄O₈Na 639.3370, found 639.3371.

Methyl(2S,5S,8S)-2-allyl-8-(4-allyloxybenzyl)-3,6,9-triaza-5-(4-[{di-tert-butoxycarbonyl}guanidino]pentyl)-4,7,10-trioxoundecanoate(195)

To a solution of 192 (20 mg, 0.032 mmol) in DCM (2 mL) was added TFA (2mL) and the resulting mixture was allowed to stir for 3 h. The solventwas removed and the oily intermediate was solidified upon the additionof diethyl ether (5 mL) which was decanted and the solid product wasdried in vacuo. To the remaining salt was addedN1-tert-butoxycarboxamido(trifluoromethylsulfonylimino)methylpropanamide (34 mg, 0.086 mmol), triethylamine (0.1 mL) and DCM (2 mL).The resulting solution was allowed to stir for 16 h under N₂. Thesolvent was removed and the crude product was purified by flashchromatography (20:1, DCM/MeOH) to yield the title compound (23 mg,0.030 mmol, 95%) as a clear oil. ¹H NMR (CDCl₃, 300 MHz): δ 8.31 (bs,1H, NH); 7.08 (d, J=8.7 Hz, 2H, ArH2′″ and ArH6′″); 6.82 (d, J=8.7 Hz,2H, ArH3′″ and ArH5′″); 6.72 (d, J=8.1 Hz, 1H, NH); 6.60 (d, J=7.5 Hz,1H, NH); 6.41 (d, J=7.8 Hz, 1H, NH); 6.03 (m, 1H, H2″″); 5.65 (m, 1H,H2′); 5.40 (dd, J=1.5, 17.1 Hz, 1H, H3_(a)″″); 5.27 (dd, 1.5, 10.5 Hz,1H, H3_(b)″″); 5.11 (m, 2H, H3′); 4.66 (m, 1H, H2); 4.57 (m, 1H, H5);4.49 (m, 2H, H1″″); 4.38 (m, 1H, H8); 3.74 (s, 3H, OCH₃); 3.34 (m, 2H,H5″); 2.98 (m, 2H, ArCH₂); 2.52 (m, 2H, H1′); 1.97 (s, 3H, H111); 1.80(m, 2H, H1″); 1.70 (m, 2H, H3″); 1.49 (s, 18H, C(CH₃)₃); 1.32 (m, 4H,H2″ and H4″). Mass Spectrum (ES, +ve) m/z 759 (100%) [MH⁺]. HRMS calcdfor C₃₈H₅₉N₆O₁₀ 759.4293, found 759.4272.

Methyl(2S,5S,8S)-2-allyl-8-(4-allyloxybenzyl)-3,6,9-triaza-5-(4-guanidinopentyl)-4,7,10-trioxoundecanoatehydrochloride (168)

The title compound was synthesized using the general N-Boc deprotectionprocedure (Procedure A) from 195 (20 mg, 0.026 mmol) to yield 168 (10mg, 0.017 mmol, 65%) as a white hydroscopic solid. ¹H NMR (CDCl₃, 300MHz): δ 7.13 (d, J=8.4 Hz, 2H, ArH2′″ and ArH6′″); 6.82 (d, J=8.4 Hz,2H, ArH3′″ and ArH5′″); 6.03 (m, 1H, H2″″); 5.76 (m, 1H, H2′); 5.37 (dd,J=1.5, 17.1 Hz, 1H, H3_(a)″″); 5.22 (dd, 1.5, 10.5 Hz, 1H, H3_(b)″″);5.10 (m, 2H, H3′); 4.50 (m, 2H, H1″″); 4.38 (m, 3H, H2, H5 and H8); 3.69(s, 3H, OCH₃); 3.15 (m, 2H, H5″); 2.92 (m, 2H, ArCH₂); 2.51 (m, 2H,H1′); 1.90 (s, 3H, H11); 1.78 (m, 2H, H1″); 1.58 (m, 2H, H3″); 1.38 (m,4H, H2″ and H4″). ¹³C NMR (CDCl₃, 75 MHz): δ 174.1, C7; 173.8, C1;173.3, C4; 168.9, C10; 159.0, CN₃; 158.6, ArC4′″; 134.4, C2′; 131.4,C2″″; 131.2, ArCH2′″ and ArCH6′″; 130.4, ArC1′″; 118.9, C3′; 117.4,C3″″; 115.7, ArCH3′″ and ArCH5′″; 69.8, C1″″; 56.5, C5; 54.1, OCH₃;53.6, C8; 52.7, C2; 42.2, C5″; 37.9, ArCH₂; 36.7, C1′; 33.1, C1″; 29.6,C4″; 27.1, C3″; 26.0, C11; 22.3, C2″. Mass Spectrum (ES, +ve) m/z 559(100%) [M⁺]. HRMS calcd for C₂₈H₃N₆O₆ 559.3244, found 559.3226.

Antibacterial Screening Methodology for Compounds of Example 2

Bacterial Strain

-   -   All assays used the Staphylococcus aureus strain ATCC 6538P.    -   Assays described in Chapter 5 additionally used the        vancomycin-resistant enterococci and vancomycin-sensitive        enterococci strains Ef243, Ef449, Ef820 and Ef487.        Culture Media    -   Mueller-Hinton Broth Medium (MHB): MHB (Oxoid CM405) was        prepared with final concentrations of 1 μl/mL MgCl₂ and 2 μg/mL        CaCl₂. Culture medium was pre-warmed for approximately 2-3 h at        37° C. before use.    -   Mueller-Hinton Agar Medium (MHA): MMB containing 1.5% Agar        (Merck Agar 1.01614).        Maintenance of Bacteria    -   From a thawed cryovial, the bacteria was streaked onto MHA and        the plate incubated overnight at 37° C.    -   From this plate, 10 cryovials were prepared by looping several        colonies into 0.5 mL of 20% glycerol solution. The cryovials        were immediately stored at −140° C.        Preparation of Seed Cultures    -   A cryovial was removed from −140° C. storage and thawed at room        temperature.    -   An MHA plate was streaked with a loopful of bacterial suspension        and incubated overnight at 37° C. to create a parent plate (P1).    -   A daughter plate (D1) was streaked from the parent plate and        incubated overnight at 37° C. The parent plate was stored at 4°        C.    -   A loop of colony from the daughter plate was used to innoculate        a 125 mL flask containing 20 mL of MHB containing 25 μg/mL        CaCl₂.2H₂O and 12.5 μg/mL MgCl₂.6H₂O.    -   The flask was shaken at 260 rpm for 18 h at 37° C. on an orbital        incubator shaker.    -   The parent plate (P1) was reused within 9 days to generate        another daughter plate (D2), which was used to inoculate a broth        culture.    -   Parent plates were used twice (to generate D1 and D2 plates)        before a new one was prepared from the previously thawed        cryovial. The second parent plate (P2) was used to generate two        additional daughter plates using the procedure outlined above        before being discarded.    -   Cryovials were used twice to prepare parent plates (P1 and P2)        before being discarded.        Preparation of Standardized Inocula for Assays    -   A 1/10 dilution of seed cultures was prepared by adding 250 μL        of the cultures to 2,250 μL of MHB in a disposable cuvette.    -   The OD₆₅₀ was read and multiplied by a factor of 10 to calculate        the optical density of the undiluted culture.    -   The required dilution factor for the preparation of standardized        inocula was calculated by dividing the observed OD₆₅₀ by the        standard OD₆₅₀ (previously determined as an OD₆₅₀ of 4.75 from        optimization studies).    -   A 10 mL sample of standardized inocula was prepared as        illustrated by the following example:        Sample Calculation:        OD₆₅₀=0.492( 1/10 dilution)        10×0.492=4.92        as; 4.75/4.92=0.97    -   Add 0.97 mL of S. aureus seed culture to 9.03 mL of MHB as the        first dilution.    -   Sufficient volumes of the final inoculum cultures were prepared        in pre-warmed MHB (37° C.) by diluting the standardized cultures        to the required final concentration (S. aureus required a 108        dilution).        Assay Procedure (for 96-Well Microtitre Plates)    -   To each well of the 96-well microtitre plate was added 50 μL of        liquid medium.    -   The peptoid compounds to be tested were dissolved in a 50%        MeOH/H₂O solution to give a concentration of 1 mg/mL    -   50 μL of test solution was added in triplicate to the top row of        the microtitre plate (2 peptoid samples were tested per plate).        A vancomycin control set (triplicate) and a compound negative        control set (triplicate) were also included on each plate (FIG.        1).    -   The inoculated culture medium was incubated at 37° C. for 30        min, with shaking at 130 rpm.    -   Using a multichannel pipette, the contents of the first row were        mixed before 50 μL was transferred to the second row. The        pipette tips were changed and the process repeated by 50 μL of        the mixed broth solutions in the second row being transferred to        the third row. This process was repeated until the last row        contained either the diluted test compound or a control        (vancomycin or compound-negative). 50 μL was discarded from this        final row so that each well contained 50 μL of liquid medium.    -   Using a multistepper pipette, 50 μL of the inoculum was added to        each well of the plate except for the last row in the        compound-negative control set, which received 50 μL of liquid        broth.    -   The plates were incubated at 37° C. for 18 h, with shaking at        100 rpm in an environment of approximately 90% humidity.    -   The results were recorded as the highest dilution of test        compound that prevented bacterial growth (MIC).        Antibacterial Testing of Compounds of Example 2        Introduction

The specific testing procedures and protocols are outlined in thesection “Antibacterial Screening Methodology for the Compounds ofExample 2”. The antibacterial testing was performed on avancomycin-susceptible strain of S. aureus, and compounds that showedpromising activity were subsequently tested against a variety ofvancomycin resistant and vancomycin sensitive enterococcal strains(Enterococcus faecium) (see Chapter 5).

Antibacterial Testing Results

The antibacterial activity results are measured by minimum inhibitoryconcentration (MIC), which is the lowest concentration of compoundnecessary to prevent bacterial growth. The activities ranged from MIC7.8 μl/mL for compound 75 to MIC>125 μg/mL (inactive) for a number ofcompounds. Some testing was done in the earlier stages of the project athigher concentration ranges up to 500 μg/mL, while later testing wasperformed with an upper limit of 125 μg/mL. For consistency, activityvalues greater than 125 μl/mL have been designated inactive, whilst anactivity of 125 μg/mL is considered weakly active. Vancomycin was usedas the standard/control and typically had an MIC range of 1.25-2.5μg/mL. The antibacterial testing results for S. aureus are tabulated inTable 1.

TABLE 1 Tabulated antibacterial testing results on S. aureusAntibacterial activity Compound (MIC μg/mL) 69 125 70 125 71 125 72 12573 31.3 74 15.6 75 7.8 76 15.6 77 125 83 125 12 62.5 43 125 48 125 3262.5 37 125 65 15.6 56 125Antibacterial Testing of Linear Cationic Peptides of Example 2Introduction

The antibacterial testing was performed using the same protocols asthose used previously described in the section “Antibacterial Testing ofcompounds of Example 2”, using a vancomycin-susceptible strain of S.aureus, and an additional three strains of vancomycin-sensitive orpartially sensitive enterococci (E.f243, E.f449 and E.f987: vancomycinMIC 1.95, 62.5 and <0.98 μg/mL respectively) and one fullyvancomycin-resistant Enterrococci faecium strain (E.f820: vancomycinMIC>125 μg/mL).

Antibacterial Testing Results

The testing results again are measured by minimum inhibitoryconcentration (MIC), on a scale from 0.98 μg/mL to 125 μg/mL. Vancomycinwas used as the standard/control. The antibacterial testing results forthe linear cationic peptides are described in Tables 2 and 3

TABLE 2 Antibacterial activity μg/mL Compound S.a E.f243 E.f449 E.f820E.f987 Vancomycin 1.95 1.95 62.5 >125 <0.98 118 31.3 >125 >125 >125 >125119 15.6 >125 >125 >125 >125 120 3.9 62.5 62.5 62.5 62.5 121 7.8 125 125125 >125 132 3.9 31.3 31.3 31.3 62.5  90 1.95 31.3 31.3 31.3 31.3 1343.9 62.5 62.5 62.5 125 135 7.8 125 62.5 62.5 125 136 7.8 125 62.5 62.5125 137 3.9 62.5 31.3 31.3 62.5 138 3.9 31.3 15.6 15.6 31.3 13915.6 >125 >125 >125 >125 140 7.8 >125 >125 >125 >125 141 3.9 31.3 31.331.25 62.5

TABLE 3 Antibacterial activity μg/mL Compound S.a E.f243 E.f449 E.f820E.f987 155 7.8 >125 125 125 >125 156 3.9 125 125 62.5 62.5 157 15.6 >125125 125 >125 158 7.8 62.5 62.5 31.3 62.5 159 62.5 125 125 62.5 >125 1607.8 62.5 62.5 62.5 125 161 15.6 — — 62.5 — 162 3.9 >125 >125 >125 >125163 15.6 >125 >125 >125 >125 164 7.8 >125 >125 >125 >125Testing of Compounds of Example 2 Against the HIV Integrase EnzymeHIV Integrase Initial Screening Results

Compounds synthesized in Example 2 were additionally included in arandom database screening strategy against the HIV integrase enzyme.

The compounds that were chosen to be tested against HIV integrase were78, 81, 88 and 89 and the results are represented in Table 4.

TABLE 4 Compound Conc. (μg/mL) % Inhibition 78 50 15% 81 50 70% 88 5095% 89 50  4%

These results represent promising hits as the compounds aresignificantly different in structure from previously known HIV integraseinhibitors. These results formed a preliminary set of structure activityrelationships (SAR's) with regard to the stereochemistry of the aminoacid residues and the length and functionality of the basic side-chain.

Testing Against the HIV Integrase Enzyme

The results for the screening of the four target molecules 165-168against the HIV integrase enzyme yielded some encouraging results whichsupported the proposed mechanism of binding in the active binding trenchof the HIV integrase enzyme. The testing procedure for the four targetcompounds differed from the original screening protocols employed. Theoriginal screening measured inhibition against the 3′ processingfunction of the enzyme at the fixed concentration of 50 μg/mL, whereasthe four target molecules were tested in an assay adapted from aliterature procedure,¹⁰⁷ which measures inhibition against the 3′ strandtransfer function of the enzyme. This allows a result to be obtained asan inhibition constant (IC₅₀) concentration, which is the standardmeasurement of inhibition within the literature. Along with the fourtarget molecules, 88 was also re-tested in the 3′ strand transfer assayto determine the IC₅₀ for direct comparison with the literature. Theresults for the testing of the four target molecules and the re-testingof 88 against HIV integrase are summarized in Table 5.

TABLE 5 Compound 88

165

166

167

168

After these compounds and the computer modelling studies had becomeestablished, all compounds that were sent for screening in theantibacterial assay were then also cross tested for their ability toinhibit the HIV integrase enzyme. Several compounds are active withmoderate levels of inhibition and compound 163, one of the hydroxamicacid binaphthyl derivatives, appears to be almost as active as theoriginal lead 88, and is again structurally unique with the largehydrophobic binaphthyl moiety. The results of these compounds aresummarized in Table 6.

TABLE 6 Compound 83

119

164

163

158

Throughout this specification the word “comprise”, or variations such as“comprises” or “comprising”, will be understood to imply the inclusionof a stated element, integer or step, or group of elements, integers orsteps, but not the exclusion of any other element, integer or step, orgroup of elements, integers or steps.

All publications mentioned in this specification are herein incorporatedby reference. Any discussion of documents, acts, materials, devices,articles or the like which has been included in the presentspecification is solely for the purpose of providing a context for thepresent invention. It is not to be taken as an admission that any or allof these matters form part of the prior art base or were common generalknowledge in the field relevant to the present invention as it existedanywhere before the priority date of each claim of this application.

It will be appreciated by persons skilled in the art that numerousvariations and/or modifications may be made to the invention as shown inthe specific embodiments without departing from the spirit or scope ofthe invention as broadly described. The present embodiments are,therefore, to be considered in all respects as illustrative and notrestrictive.

REFERENCES

-   (1) Dineen, P.; Homan, W. P.; Grafe, W. R. Annals of Surgery 1976,    184, 717-22.-   (2) Neu, H. C. Science 1992, 257, 1064-72.-   (3) Nicolaou, K. C.; Boddy, C. N. C. Sci. Am. 2001, 284, 54-61.-   (4) Noble, W. C.; Virani, Z.; Cree, R. G. A. FEMS Microbiol. Lett.    1992, 93, 195-8.-   (5) Guiot, H. F.; Peetermans, W. E.; Sebens, F. W. Eur. J. Clin.    Microbiol. Infect. Dis. 1991, 10, 32-4.-   (6) Handwerger, S.; Raucher, B.; Altarac, D.; Monka, J.; Marchione,    S.; Singh, K. V.; Murray, B. E.; Wolff, J.; Walters, B. Clin.    Infect. Dis. 1993, 16, 750-5.-   (7) Sievert, D. M. Morbid. Mortal. Wkly Rep. 2002, 51, 565-7.-   (8) Daly, J. S.; Eliopoulos, G. M.; Willey, S.; Moellering, R. C.,    Jr. Antimicrob. Agents Chemother. 1988, 32, 1341-6.-   (9) Tsiodras, S.; Gold, H. S.; Sakoulas, G.; Eliopoulos, G. M.;    Wennersten, C.; Venkataraman, L.; Moellering, R. C.; Ferraro, M. J.    Lancet 2001, 358, 207-8.-   (10) Gonzales, R. D.; Schreckenberger, P. C.; Graham, M. B.; Kelkar,    S.; DenBesten, K.; Quinn, J. P. Lancet 2001, 357, 1179.-   (11) Halls, G. The Complete Guide to Anti-infectives; PJB    Publications: Richmond Surrey UK, 1999.-   (12) Stover, C. K.; Pham, X. Q.; Erwin, A. L.; Mizoguchi, S. D.;    Warrener, P.; Hickey, M. J.; Brinkman, F. S.; Hufnagle, W. O.;    Kowalik, D. J.; Lagrou, M.; Garber, R. L.; Goltry, L.; Tolentino,    E.; Westbrock-Wadman, S.; Yuan, Y.; Brody, L. L.; Coulter, S. N.;    Folger, K. R.; Kas, A.; Larbig, K.; Lim, R.; Smith, K.; Spencer, D.;    Wong, G. K.; Wu, Z.; Paulsen, I. T.; Reizer, J.; Saieri, M. H.;    Hancock, R. E.; Lory, S.; Olson, M. V. Nature 2000, 406, 959-64.-   (13) Perna, N. T.; Plunkett, G., 3rd; Burland, V.; Mau, B.;    Glasner, J. D.; Rose, D. J.; Mayhew, G. F.; Evans, P. S.; Gregor,    J.; Kirkpatrick, H. A.; Posfai, G.; Hackett, J.; Klink, S.; Boutin,    A.; Shao, Y.; Miller, L.; Grotbeck, E. J.; Davis, N. W.; Lim, A.;    Dimalanta, E. T.; Potamousis, K. D.; Apodaca, J.; Anantharaman, T.    S.; Lin, J.; Yen, G.; Schwartz, D. C.; Welch, R. A.; Blattner, F. R.    Nature 2001, 409, 529-33.-   (14) Kuroda, M.; Ohta, T.; Uchiyama, I.; Baba, T.; Yuzawa, H.;    Kobayashi, I.; Cui, L.; Oguchi, A.; Aoki, K.; Nagai, Y.; Lian, J.;    Ito, T.; Kanamori, M.; Matsumaru, H.; Maruyama, A.; Murakami, H.;    Hosoyama, A.; Mizutani-Ui, Y.; Takahashi, N. K.; Sawano, T.; Inoue,    R.; Kaito, C.; Sekimizu, K.; Hirakawa, H.; Kuhara, S.; Goto, S.;    Yabuzaki, J.; Kanehisa, M.; Yamashita, A.; Oshima, K.; Furuya, K.;    Yoshino, C.; Shiba, T.; Hattori, M.; Ogasawara, N.; Hayashi, H.;    Hiramatsu, K. Lancet 2001, 357, 1225-40.-   (15) Payne, D. J.; Wallis, N. G.; Gentry, D. R.; Rosenberg, M. Curr.    Opin. Drug Discovery & Development 2000, 3, 177-90.-   (16) Searls, D. B. Drug Discovery Today 2000, 5, 135-143.-   (17) Moir, D. T.; Shaw, K. J.; Hare, R. S.; Vovis, G. F. Antimicrob.    Agents Chemother. 1999, 43, 439-46.-   (18) Loferer, H. Mol. Med. Today 2000, 6, 470-4.-   (19) Dessen, A.; Mouz, N.; Gordon, E.; Hopkins, J.; Dideberg, O. J.    Biol. Chem. 2001, 276, 45106-12.-   (20) Dowson, C. G.; Hutchison, A.; Brannigan, J. A.; George, R. C.;    Hansman, D.; Linares, J.; Tomasz, A.; Smith, J. M.; Spratt, B. G.    Proc. Natl. Acad. Sci. USA 1989, 86, 8842-6.-   (21) Severin, A.; Figueiredo, A. M. S.; Tomasz, A. J. Bacteriol.    1996, 178, 1788-92.-   (22) Bush, K.; Jacoby, G. A.; Medeiros, A. A. Antirnicrob. Agents    Chemother. 1995, 39, 1211-33.-   (23) Swaren, P.; Golemi, D.; Cabantous, S.; Bulychev, A.; Maveyraud,    L.; Mobashery, S.; Samama, J. P. Biochemistry 1999, 38, 9570-6.-   (24) Blanpain, P. C.; Nagy, J. B.; Laurent, G. H.; Durant, F. V. J.    Med. Chem. 1980, 23, 1283-92.-   (25) Lee, W.; McDonough, M. A.; Kotra, L. P.; Li, Z.-H.;    Silvaggi, N. R.; Takeda, Y.; Kelly, J. A.; Mobashery, S. Proc. Natl.    Acad. Sci. USA 2001, 98, 1427-31.-   (26) McCormick, M., Stark, W. M., Pittenger, G. E., Pittenger, R. C.    and McGuire, J. M.; Welch, H. a. M.-I., F., Ed.; Medical    Encyclopedia: New York, 1956, p 606-11.-   (27) Griffith, R. S. a. P., F. GB.; Welsh, H. a. M.-I., F., Ed.;    Medical Encyclopedia: New York, 1956, p 619-22.-   (28) Anderson, R. C., Worth, H. M., Harris, P. N., and Chen, K. K.;    Welch, H. a. M.-I., F., Ed.; Medical Encyclopedia: New York, 1957, p    75-81.-   (29) Harris, C. M.; Harris, T. M. J. Am. Chem. Soc. 1982, 104,    4293-5.-   (30) Marshall, F. J. J. Med. Chem. 1965, 8, 18-22.-   (31) Williams, D. H.; Kalman, J. J. Am. Chem. Soc. 1977, 99,    2768-74.-   (32) Sheldrick, G. M.; Jones, P. G.; Kennard, O.; Williams, D. H.;    Smith, G. A. Nature 1978, 271, 223-5.-   (33) Kaplan, J.; Korty, B. D.; Axelsen, P. H.; Loll, P. J. J. Med.    Chem. 2001, 44, 1837-40.-   (34) Ge, M.; Chen, Z.; Onishi, H. R.; Kohler, J.; Silver, L. L.;    Kerns, R.; Fukuzawa, S.; Thompson, C.; Kahne, D. Science 1999, 284,    507-11.-   (35) Williams, D. H., Westwell, M. S., Beauregard, D. A.,    Sharman, G. J., Dancer, R. J., Try, A. C., and Bardsley, B. in    Anti-infectives. Recent Advances in Chemistry and Structure Activity    Relationships (Bently, P. H.; O'HAnlon, P. J.) Royal Society of    Chem., Cambridge., 1997, p 3-14.-   (36) Williams, D. H.; Williamson, M. P.; Butcher, D. W.; Hammond, S.    J. J. Am. Chem. Soc. 1983, 105, 1332-9.-   (37) Gale, T. F.; Gorlitzer, J.; O'Brien, S. W.; Williams, D. H. J.    Chem. Soc., Perkin Trans. 1 1999, 2267-70.-   (38) Wright, G. D.; Walsh, C. T. Acc. Chem. Res. 1992, 25, 468-73.-   (39) Gold, H. S.; Moellering, R. C., Jr. New Engl. J. Med. 1996,    335, 1445-53.-   (40) Sussmuth, R. D. Chem Bio Chem 2002, 3, 295-8.-   (41) Beauregard, D. A.; Williams, D. H.; Gwynn, M. N.;    Knowles, D. J. Antimicrob. Agents Chemother. 1995, 39, 781-5.-   (42) Westwell, M. S.; Gerhard, U.; Williams, D. H. J. Antibiot.    1995, 48, 1292-8.-   (43) Slee, A. M.; Wuonola, M. A.; McRipley, R. J.; Zajac, I.;    Zawada, M. J.; Bartholomew, P. T.; Gregory, W. A.; Forbes, M.    Antimicrob. Agents Chemother. 1987, 31, 1791-7.-   (44) Nicas, T. I.; Zeckel, M. L.; Braun, D. K. Trends Microbiol.    1997, 5, 240-9.-   (45) Eliopoulos, G. M.; Wennersten, C. B.; Gold, H. S.;    Moellering, R. C., Jr. Antimicrob. Agents Chemother. 1996, 40,    1745-7.-   (46) Ford, C. W.; Hamel, J. C.; Stapert, D.; Moerman, J. K.;    Hutchinson, D. K.; Barbachyn, M. R.; Zurenko, G. E. Trends    Microbiol. 1997, 5, 196-200.-   (47) Ford, C. W.; Hamel, J. C.; Wilson, D. M.; Moerman, J. K.;    Stapert, D.; Yancey, R. J., Jr.; Hutchinson, D. K.; Barbachyn, M.    R.; Brickner, S. J. Antimicrob. Agents Chemother. 1996, 40, 1508-13.    2416-9.-   (51) Jones, R. N.; Barrett, M. S.; Erwin, M. E. Antimicrob. Agents    Chemother. 1997, 41, 488-93.-   (52) Zelenitsky, S. A.; Karlowsky, J. A.; Zhanel, G. G.; Hoban, D.    J.; Nicas, T. Antimicrob. Agents Chemother. 1997, 41, 1407-8.-   (53) Baltch, A. L.; Smith, R. P.; Ritz, W. J.; Bopp, L. H.    Antimicrob. Agents Chemother. 1998, 42, 2564-8.-   (54) Kems, R.; Dong, S. D.; Fukuzawa, S.; Carbeck, J.; Kohler, J.;    Silver, L.; Kahne, D. J. Am. Chem. Soc. 2000, 122, 12608-9.-   (55) Ge, M.; Chen, Z.; Onishi, H. R.; Kohler, J.; Silver, L. L.;    Kems, R.; Fukuzawa, S.; Thompson, C.; Kahne, D. Science 1999, 284,    507-11.-   (56) Van Heijenoort, J. Glycobiol. 2001, 11, 25R-36R.-   (57) Wang, Q. M.; Peery, R. B.; Johnson, R. B.; Albom, W. E.;    Yeh, W. K.; Skatrud, P. L. J. Bacteriol. 2001, 183, 4779-85.-   (58) Sundram, U. N.; Griffin, J. H.; Nicas, T. I. J. Am. Chem. Soc.    1996, 118, 13107-8.-   (59) Hinzen, B.; Seiler, P.; Diederich, F. Helv. Chim. Acta. 1996,    79, 942-60.-   (60) Xu, R.; Greiveldinger, G.; Marenus, L. E.; Cooper, A.;    Ellman, J. A. J. Am. Chem. Soc. 1999, 121, 4898-9.-   (61) Miller, C. T.; Weragoda, R.; Izbicka, E.; Iverson, B. L.    Bioorg. Med. Chem. 2001, 9, 2015-24.-   (62) Monnee, M. C. F.; Brouwer, A. J.; Verbeek, L. M.; van    Wageningen, A. M. A.; Liskamp, R. M. J. Bioorg. Med. Chem. Lett.    2001, 11, 1521-5.-   (63) Chiosis, G.; Boneca, I. G. Science 2001, 293, 1484-7.-   (64) Hoffmann, J. A.; Kafatos, F. C.; Janeway, C. A.;    Ezekowitz, R. A. Science 1999, 284, 1313-8.-   (65) Thennarasu, S.; Nagaraj, R. Biochem. Biophys. Res. Commun.    1999, 254, 281-283.-   (66) Saido-Sakanaka, H.; Ishibashi, J.; Sagisaka, A.; Momotani, E.;    Yamakawa, M. Biochem. J. 1999, 338, 29-33.-   (67) Tossi, A.; Tarantino, C.; Romeo, D. Eur. J. Biochem. 1997, 250,    549-58.-   (68) Strom, M. B.; Rekdal, O.; Svendsen, J. S. J. Pept. Res. 2000,    56, 265-74.-   (69) Haug, B. E.; Svendsen, J. S. J. Pept. Sci. 2001, 7, 190-6.-   (70) Haug, B. E.; Skar, M. L.; Svendsen, J. S. J. Pept. Sci. 2001,    7, 425-32.-   (71) Strom, M. B.; Rekdal, O.; Svendsen, J. S. J. Pept. Sci. 2002,    8, 431-7.-   (72) Strom, M. B.; Haug, B. E.; Skar, M. L.; Stensen, W.; Stiberg,    T.; Svendsen, J. S. J. Med. Chem. 2003, 46, 1567-70.-   (73) Mosca, D. A.; Hurst, M. A.; So, W.; Viajar, B. S.; Fujii, C.    A.; Falla, T. J. Antimicrob. Agents Chemother. 2000, 44, 1803-8.-   (74) Toney, J. H. Cur. Opin. Invest. Drugs 2002, 3, 225-8.-   (75) Oh, H.-S.; Kim, S.; Cho, H.; Lee, K.-H. Bioorg. Med. Chem.    Lett. 2004, 14, 1109-13.-   (76) Houghten, R. A.; Pinilla, C.; Blondelle, S. E.; Appel, J. R.;    Dooley, C. T.; Cuervo, J. H. Nature 1991, 354, 84-6.-   (77) Abiraj, K.; Prakasha Gowda, A. S.; Channe Gowda, D. Lett. Pept.    Sci. 2003, 9, 283-90.-   (78) Bremner, J. B.; Coates, J. A.; Coghlan, D. R.; David, D. M.;    Keller, P. A.; Pyne, S. G. N. J. Chem. 2002, 26, 1549-51.-   (79) Bremner, J. B.; Coates, J. A.; Keller, P. A.; Pyne, S. G.;    Witchard, H. M. Synlett 2002, 219-22.-   (80) Bremner, J. B.; Coates, J. A.; Keller, P. A.; Pyne, S. G.;    Witchard, H. M. Tetrahedron 2003, 59, 8741-55.-   (81) Bremner, J. B.; Pyne, S. G.; Keller, P. A.; Coghlan, D. R.,    Personal Communication.-   (82) McGrady, K. A. W.; Overberger, C. G. Polymer J. 1987, 19,    539-55.-   (83) Gamet, J. P.; Jacquier, R.; Verducci, J. Tetrahedron 1984, 40,    1995-2001.-   (84) Luening, B.; Norberg, T.; Tejbrant, J. Chem. Commun. 1989,    1267-8.-   (85) Schuster, M.; Blechert, S. Angew. Chem. Int. Ed. 1997, 36,    2037-56.-   (86) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-29.-   (87) Brummer, O.; Ruckert, A.; Blechert, S. Chem. Europ. J. 1997, 3,    441-6.-   (88) Grubbs, R. H.; Miller, S. J.; Blackwell, H. E.; (California    Institute of Technology, USA). Application: US, 1998, 21 pp.-   (89) Miller, S. J.; Blackwell, H. E.; Grubbs, R. H. J. Am. Chem.    Soc. 1996, 118, 9606-14.-   (90) Miller, S. J.; Grubbs, R. H. J. Am. Chem. Soc. 1995, 117,    5855-6.-   (91) Feichtinger, K.; Zapf, C.; Sings, H. L.; Goodman, M. J. Org.    Chem. 1998, 63, 3804-5.-   (92) Weerapana, E.; Imperiali, B. Org. Biomol. Chem. 2003, 1, 93-9.-   (93) Lei, H.; Stoakes, M. S.; Schwabacher, A. W.; Herath, K. P. B.;    Lee, J. J. Org. Chem. 1994, 59, 4206-10.-   (94) Morera, E.; Ortar, G. Synlett 1997, 1403-5.-   (95) Wilbur, D. S.; Hamlin, D. K.; Srivastava, R. R.; Burns, H. D.    Biocon. Chem. 1993, 4, 574-80.-   (96) Stille, J. K. Angew. Chem. 1986, 98, 504-19.-   (97) Burke, T. R., Jr.; Fesen, M. R.; Mazumder, A.; Wang, J.;    Carothers, A. M.; Grunberger, D.; Driscoll, J.; Kohn, K.;    Pommier, Y. J. Med. Chem. 1995, 38, 4171-8.-   (98) Yi, J.; Arthur, J. W.; Dunbrack, R. L., Jr.; Skalka, A. M. J.    Biol. Chem. 2000, 275, 38739-48.-   (99) Andrake, M. D.; Skalka, A. M. J. Biol. Chem. 1996, 271,    19633-6.-   (100) O'Brien, C. Science 1994, 266, 1946.-   (101) Hickman, A. B.; Palmer, I.; Engelman, A.; Craigie, R.;    Wingfield, P. J. Biol. Chem. 1994, 269, 29279-87.-   (102) Goldgur, Y.; Craigie, R.; Cohen, G. H.; Fujiwara, T.;    Yoshinaga, T.; Fujishita, T.; Sugimoto, H.; Endo, T.; Murai, H.;    Davies, D. R. Proc. Natl. Acad. Sci. USA 1999, 96, 13040-3.-   (103) Modelling studies were performed by AMRAD in collaboration    with the Victorian College of Pharmacy. For experimental details and    docking procedures see: Wielens, J. PhD Thesis, Victorian College of    Pharmacy (Monash University), 2004.-   (104) van Benthem, R. A. T. M.; Michels, J. J.; Hiemstra, H.;    Speckamp, W. N. Synlett 1994, 368-70.-   (105) Beaulieu, P. L.; Schiller, P. W. Tetrahedron Lett. 1988, 29,    2019-22.-   (106) Dong, Z. Tetrahedron Lett. 1992, 33, 7725-6.-   (107) Hwang, Y.; Rhodes, D.; Bushman, F. Nucl. Acids Res. 2000, 28,    4884-92.-   (108) Nieto, M.; Perkins, H. R. Biochem. J. 1971, 123, 789-803.-   (109) Mackay, J. P.; Gerhard, U.; Beauregard, D. A.; Williams, D.    H.; Westwell, M. S.; Searle, M. S. J. Am. Chem. Soc. 1994, 116,    4581-90.-   (110) Linsdell, H.; Toiron, C.; Bruix, M.; Rivas, G.;    Menendez, M. J. Antibiot. 1996, 49, 181-93.-   (111) Searle, M. S.; Sharman, G. J.; Groves, P.; Benhamu, B.;    Beauregard, D. A.; Westwell, M. S.; Dancer, R. J.; Maguire, A. J.;    Try, A. C.; Williams, D. H. J. Chem. Soc., Perkin Trans. 1 1996,    2781-6.-   (112) Dancer, R. J.; Try, A. C.; Sharman, G. J.; Williams, D. H.    Chem. Commun. 1996, 1445-6.-   (113) Allen, N. E.; LeTourneau, D. L.; Hobbs, J. N., Jr. Antimicrob.    Agents Chemother. 1997, 41, 66-71.-   (114) Barna, J. C. J.; Williams, D. H.; Williamson, M. P. Chem.    Commun. 1985, 254-6.-   (115) Williamson, M. P.; Williams, D. H.; Hammond, S. J. Tetrahedron    1984, 40, 569-77.-   (116) Rodriguez-Tebar, A.; Vazquez, D.; Perez Velazquez, J. L.;    Laynez, J.; Wadso, I. J. Antibiot. 1986, 39, 1578-83.-   (117) Jorgensen, T. J. D.; Staroske, T.; Roepstorff, P.;    Williams, D. H.; Heck, A. J. R. J. Chem. Soc., Perkin Trans. 2 1999,    1859-63.-   (118) Jorgensen, T. J. D.; Roepstorff, P.; Heck, A. J. R. Anal.    Chem. 1998, 70, 4427-32.-   (119) Van de Kerk-Van Hoof, A.; Heck, A. J. R. J. Antimicrob.    Chemother. 1999, 44, 593-9.-   (120) Perrin, D. D. A., W. L. F. Purification of Laboratory    Chemicals; 3rd ed.; Pergamon Press Ltd.: Oxford, 1988.-   (121) Hellwinkel, D. Systematic Nomenclature of Organic Chemistry;    1st ed.; Springer: Berlin, 2001.-   (122) Tous, G.; Bush, A.; Tous, A.; Jordan, F. J. Med. Chem. 1990,    33, 1620-34.-   (123) Meyer, L.; Poirier, J.-M.; Duhamel, P.; Duhamel, L. J. Org.    Chem. 1998, 63, 8094-5.-   (124) Pearson, A. J.; Bruhn, P. R. J. Org. Chem. 1991, 56, 7092-7.-   (125) Pirrung, M. C.; Shuey, S. W. J. Org. Chem. 1994, 59, 3890-7.-   (126) Erickson, S. D.; Simon, J. A.; Still, W. C. J. Org. Chem.    1993, 58, 1305-8.-   (127) Ma, D.; Tang, W.; Kozikowski, A. P.; Lewin, N. E.;    Blumberg, P. M. J. Org. Chem. 1999, 64, 6366-73.-   (128) Abbott, S. D.; Lane-Bell, P.; Sidhu, K. P. S.;    Vederas, J. C. J. Am. Chem. Soc. 1994, 116, 6513-20.

1. A compound of formula Ia

or a pharmaceutically acceptable salt thereof, wherein Q₁ and Q₂ areeach independently selected from hydrogen, C₁-C₁₂alkyl, C₃-C₆cycloalkyl,C₁-C₁₂alkyloxy, nitro, halogen, hydroxyl, amino, mono or dialkylamino,carboxylic acid or a salt or ester thereof, sulphonic acid or a salt orester thereof, phosphoric acid or a salt or ester thereof, carboxamide,sulphonamide and phosphoramide wherein each C₁-C₁₂alkyl,C₃-C₆cycloalkyl, or C₁-C₁₂alkyloxy is optionally substituted withhydroxyl, amino, carboxylic acid or a salt or ester thereof, sulphonicacid or a salt or ester thereof, phosphoric acid or a salt or esterthereof, or carboxamide, sulphonamide or phosphoramide; B is selectedfrom —O—, —S—, —S(O)—, —S(O)₂—, —NH—, and —N(C₁-C₆alkyl)-; R₁ isselected from hydrogen, C₁-C₁₂alkyl, C₁-C₆alkylC₃-C₆cycloalkyl,C₁-C₆alkylC₆-C₁₀aryl, C₂-C₆alkenyl, C₂-C₆alkynyl, a polyoxyalkylenehaving from 2 to 6 carbon atoms, and when B is —S—, —S(O)—, —S(O)₂—,—NH— or —N(C₁-C₆alkyl)- then R₁ may be hydroxyl; V is a linker groupselected from —O—, —O-L-C(O), —O-L-NR₆—, —C(O)—, —NR₆—, —S(O)—, —S(O)₂—,—O-L-S(O)—, —S(O)₂-L-C(O)—, —S(O)₂-L-NR₆—, P(O)₂O—; wherein L isselected from C₁-C₁₂alkyl, C₂-C₈ alkenyl, C₃-C₆cycloalkyl,polyoxyalkylene having from 2 to 6 carbon atoms, C₆-C₁₀aryl andC₁-C₆alkylC₆-C₁₀aryl; and wherein R₆ is selected from H and C₁-C₁₂alkyl;S₁ and S₂ are absent; A₁ is lysine or ornithine; A₂ is arginine; S₃ isan amino acid; and T is absent or is selected from —C(O)R₈, —C(O)OR₈,—OR₈, —NHR₈, NHOR₈, —NH—C₆aryl-CO—R₈, —NH—C₆aryl-CO—NHR₈,—NH—C₆aryl-CONHOR₈, —NH—C₆aryl-CONHOH, —C(O)NHR₈, —(NH)—SO₂C₆aryl, and—(NH)COR₈, or T forms a carboxylate isostere, optionally substitutedwith R₈, which replaces the carboxylic acid group of the amino acid towhich T is connected; wherein R₈ is selected from hydrogen, C₁-C₁₂alkyl,C₁-C₆alkylC₆-C₁₀aryl, C₁-C₆alkylC₃-C₆cycloalkyl, C₂-C₆alkenyl andC₂-C₆alkynyl; and wherein when T is connected to the C-terminus of anamino acid residue then the carbonyl group of the amino acid residue maybe reduced to methylene.
 2. A compound of formula Ib

or a pharmaceutically acceptable salt thereof, wherein Q₁ and Q₂ areeach independently selected from hydrogen, C₁-C₁₂alkyl, C₃-C₆cycloalkyl,C₁-C₁₂alkyloxy, nitro, halogen, hydroxyl, amino, mono or dialkylamino,carboxylic acid or a salt or ester thereof, sulphonic acid or a salt orester thereof, phosphoric acid or a salt or ester thereof, carboxamide,sulphonamide and phosphoramide wherein each C₁-C₁₂alkyl,C₃-C₆cycloalkyl, or C₁-C₁₂alkyloxy is optionally substituted withhydroxyl, amino, carboxylic acid or a salt or ester thereof, sulphonicacid or a salt or ester thereof, phosphoric acid or a salt or esterthereof, or carboxamide, sulphonamide or phosphoramide; B is selectedfrom —O—, —S—, —S(O)—, —S(O)₂—, —NH—, and —N(C₁-C₆alkyl)-; R₁ isselected from hydrogen, C₁-C₁₂alkyl, C₁-C₆alkylC₃-C₆cycloalkyl,C₁-C₆alkylC₆-C₁₀aryl, C₂-C₆alkenyl, C₂-C₆alkynyl, a polyoxyalkylenehaving from 2 to 6 carbon atoms, and when B is —S—, —S(O)—, —S(O)₂—,—NH— or —N(C₁-C₆alkyl)- then R₁ may be hydroxyl; V is a linker groupselected from —O—, —O-L-C(O), —O-L-NR₆—, —C(O)—, —NR₆—, —S(O)—, —S(O)₂—,—O-L-S(O)—, —S(O)₂-L-C(O)—, —S(O)₂-L-NR₆—, P(O)₂O—; wherein L isselected from C₁-C₁₂alkyl, C₂-C₈ alkenyl, C₃-C₆cycloalkyl,polyoxyalkylene having from 2 to 6 carbon atoms, C₆-C₁₀aryl andC₁-C₆alkylC₆-C₁₀aryl; and wherein R₆ is selected from H and C₁-C₁₂alkyl;S₁ and S₂ are absent; A₁ is lysine or ornithine; A₂ is arginine; S₃ isan amino acid; and T is absent or is selected from —C(O)R₈, —C(O)OR₈,—OR₈, —NHR₈, NHOR₈, —NH—C₆aryl-CO—R₈, —NH—C₆aryl-CO—NHR₈,—NH—C₆aryl-CONHOR₈, —NH—C₆aryl-CONHOH, —C(O)NHR₈, —(NH)—SO₂C₆aryl, and—(NH)COR₈, or T forms a carboxylate isostere, optionally substitutedwith R_(g), which replaces the carboxylic acid group of the amino acidto which T is connected; wherein R₈ is selected from hydrogen,C₁-C₁₂alkyl, C₁-C₆alkylC₆-C₁₀aryl, C₁-C₆alkylC₃-C₆cycloalkyl,C₂-C₆alkenyl and C₂-C₆alkynyl; and wherein when T is connected to theC-terminus of an amino acid residue then the carbonyl group of the aminoacid residue may be reduced to methylene.
 3. A compound selected fromthe group consisting of compounds 1-30, or a pharmaceutically acceptablesalt thereof, wherein compounds 1-30 are as follows:


4. A composition comprising a compound of claim 1 or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier oradjuvant.
 5. A composition comprising a compound of claim 2 or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or adjuvant.
 6. A composition comprising a compoundof claim 3 or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier or adjuvant.